Faculty Profiles - OHASHI, Koji

Papers - OHASHI, Koji

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Pemafibrate ameliorates renal injury through induction of FGF21 and ketone body production in male mice. International journal

Kunihiko Takahara, Noriyuki Ouchi, Tomonobu Takikawa, Yuta Ozaki, Lixin Fang, Hiroshi Kawanishi, Minako Tatsumi, Yoshimitsu Yura, Katsuhiro Kato, Mikito Takefuji, Toyoaki Murohara, Koji Ohashi

Physiological reports Vol. 13 ( 3 ) page： e70135 2025.2

Language：English Publishing type：Research paper (scientific journal)

Chronic kidney disease is a life-threatening disease worldwide. PPARα is a crucial transcriptional regulator of lipid metabolism and inflammation. Here, we examine whether a novel selective PPARα modulator, pemafibrate modulates renal injury in a model of unilateral ureteral obstruction (UUO). Administration of pemafibrate to wild-type (WT) mice led to reduction of renal dysfunction and fibrosis after UUO with accompanying increases in plasma levels of fibroblast growth factor (FGF) 21 and ketone body β-hydroxybutyrate (BHB). Treatment of WT mice with FGF21 or BHB precursor resulted in attenuation of renal fibrotic and inflammatory responses after UUO. Treatment of proximal tubular cells with FGF21 or BHB reduced expression of epithelial-mesenchymal transition markers. These findings suggest that pemafibrate could ameliorate renal damage, at least in part, by its abilities to increase the production of FGF21 and BHB.

DOI： 10.14814/phy2.70135

Soy protein β-conglycinin ameliorates pressure overload-induced heart failure by increasing short-chain fatty acid (SCFA)-producing gut microbiota and intestinal SCFAs

Furukawa, N; Kobayashi, M; Ito, M; Matsui, H; Ohashi, K; Murohara, T; Takeda, JI; Ueyama, J; Hirayama, M; Ohno, K

CLINICAL NUTRITION Vol. 43 ( 12 ) page： 124 - 137 2024.12

ALPK2 prevents cardiac diastolic dysfunction in heart failure with preserved ejection fraction. International journal

Tatsuya Yoshida, Satoya Yoshida, Kohei Inukai, Katsuhiro Kato, Yoshimitsu Yura, Tomoki Hattori, Kentaro Taki, Atsushi Enomoto, Koji Ohashi, Takahiro Okumura, Noriyuki Ouchi, Haruya Kawase, Nina Wettschureck, Stefan Offermanns, Toyoaki Murohara, Mikito Takefuji

FASEB journal : official publication of the Federation of American Societies for Experimental Biology Vol. 38 ( 22 ) page： e70192 2024.11

Language：English Publishing type：Research paper (scientific journal)

Protein phosphorylation, controlled by protein kinases, is central to regulating various pathophysiological processes, including cardiac systolic function. The dysregulation of protein kinase activity plays a significant role in the pathogenesis of cardiac systolic dysfunction. While cardiac contraction mechanisms are well documented, the mechanisms underlying cardiac diastole remain elusive. This gap persists owing to the historical focus on systolic dysfunction in heart failure research. Recently, heart failure with preserved ejection fraction (HFpEF), an age-related disease characterized by cardiac diastolic dysfunction, has emerged as a major public health concern. However, its underlying mechanism remains unclear. In this study, we investigated cardiac protein kinases by analyzing the gene expression of 518 protein kinases in human tissues. We identified alpha-kinase 2 (ALPK2) as a novel cardiac-specific atypical kinase and generated tamoxifen-inducible, cardiomyocyte-specific Alpk2-knockout mice and Alpk2-overexpressing mice. Alpk2 deficiency did not affect cardiac systolic dysfunction in the myocardial infarction model or the pressure-overload-induced heart failure model. Notably, cardiomyocyte-specific Alpk2 deficiency exacerbated cardiac diastolic dysfunction induced by aging and in the HFpEF model. Conversely, Alpk2 overexpression increased the phosphorylation of tropomyosin 1, a major regulator that binds myosin to actin, and mitigated cardiac stiffness in HFpEF. This study provides novel evidence that ALPK2 represents a potential therapeutic target for cardiac diastolic dysfunction in HFpEF and age-related cardiac impairments.

DOI： 10.1096/fj.202402103R

Protein kinase N promotes cardiac fibrosis in heart failure by fibroblast-to-myofibroblast conversion. International journal

Satoya Yoshida, Tatsuya Yoshida, Kohei Inukai, Katsuhiro Kato, Yoshimitsu Yura, Tomoki Hattori, Atsushi Enomoto, Koji Ohashi, Takahiro Okumura, Noriyuki Ouchi, Haruya Kawase, Nina Wettschureck, Stefan Offermanns, Toyoaki Murohara, Mikito Takefuji

Nature communications Vol. 15 ( 1 ) page： 7638 - 7638 2024.9

Language：English Publishing type：Research paper (scientific journal)

Chronic fibrotic tissue disrupts various organ functions. Despite significant advances in therapies, mortality and morbidity due to heart failure remain high, resulting in poor quality of life. Beyond the cardiomyocyte-centric view of heart failure, it is now accepted that alterations in the interstitial extracellular matrix (ECM) also play a major role in the development of heart failure. Here, we show that protein kinase N (PKN) is expressed in cardiac fibroblasts. Furthermore, PKN mediates the conversion of fibroblasts into myofibroblasts, which plays a central role in secreting large amounts of ECM proteins via p38 phosphorylation signaling. Fibroblast-specific deletion of PKN led to a reduction of myocardial fibrotic changes and cardiac dysfunction in mice models of ischemia-reperfusion or heart failure with preserved ejection fraction. Our results indicate that PKN is a therapeutic target for cardiac fibrosis in heart failure.

DOI： 10.1038/s41467-024-52068-0

Myonectin protects against skeletal muscle dysfunction in male mice through activation of AMPK/PGC1α pathway. International journal

Yuta Ozaki, Koji Ohashi, Naoya Otaka, Hiroshi Kawanishi, Tomonobu Takikawa, Lixin Fang, Kunihiko Takahara, Minako Tatsumi, Sohta Ishihama, Mikito Takefuji, Katsuhiro Kato, Yuuki Shimizu, Yasuko K Bando, Aiko Inoue, Masafumi Kuzuya, Shinji Miura, Toyoaki Murohara, Noriyuki Ouchi

Nature communications Vol. 14 ( 1 ) page： 4675 - 4675 2023.8

Language：English Publishing type：Research paper (scientific journal)

To maintain and restore skeletal muscle mass and function is essential for healthy aging. We have found that myonectin acts as a cardioprotective myokine. Here, we investigate the effect of myonectin on skeletal muscle atrophy in various male mouse models of muscle dysfunction. Disruption of myonectin exacerbates skeletal muscle atrophy in age-associated, sciatic denervation-induced or dexamethasone (DEX)-induced muscle atrophy models. Myonectin deficiency also contributes to exacerbated mitochondrial dysfunction and reduces expression of mitochondrial biogenesis-associated genes including PGC1α in denervated muscle. Myonectin supplementation attenuates denervation-induced muscle atrophy via activation of AMPK. Myonectin also reverses DEX-induced atrophy of cultured myotubes through the AMPK/PGC1α signaling. Furthermore, myonectin treatment suppresses muscle atrophy in senescence-accelerated mouse prone (SAMP) 8 mouse model of accelerated aging or mdx mouse model of Duchenne muscular dystrophy. These data indicate that myonectin can ameliorate skeletal muscle dysfunction through AMPK/PGC1α-dependent mechanisms, suggesting that myonectin could represent a therapeutic target of muscle atrophy.

DOI： 10.1038/s41467-023-40435-2

Adipolin protects against renal injury via PPARα-dependent reduction of inflammasome activation

Lixin Fang, Koji Ohashi, Satoko Hayakawa, Hayato Ogawa, Naoya Otaka, Hiroshi Kawanishi, Tomonobu Takikawa, Yuta Ozaki, Kunihiko Takahara, Minako Tatsumi, Mikito Takefuji, Yuuki Shimizu, Yasuko K. Bando, Yuya Fujishima, Norikazu Maeda, Iichiro Shimomura, Toyoaki Murohara, Noriyuki Ouchi

iScience Vol. 26 ( 5 ) page： 106591 - 106591 2023.5

Omentin Modulates Chronic Cardiac Remodeling After Myocardial Infarction.

Ito M, Shibata R, Ohashi K, Otaka N, Yamaguchi S, Ogawa H, Enomoto T, Masutomi T, Murohara T, Ouchi N

Circulation reports Vol. 5 ( 2 ) page： 46 - 54 2023.2

Recent progress in adipocytokine research

Ouchi, N; Ohashi, K; Murohara, T

NAGOYA JOURNAL OF MEDICAL SCIENCE Vol. 85 ( 1 ) page： 23 - 26 2023.2

Ablation of Ctrp9, Ligand of AdipoR1, and Lower Number of Cone Photoreceptors in Mouse Retina. International journal

Daiki Inooka, Yoshihiro Omori, Noriyuki Ouchi, Koji Ohashi, Yuto Kawakami, Yoshito Koyanagi, Chieko Koike, Hiroko Terasaki, Koji M Nishiguchi, Shinji Ueno

Investigative ophthalmology & visual science Vol. 63 ( 5 ) page： 14 - 14 2022.5

Language：English Publishing type：Research paper (scientific journal)

Purpose: C1q/TNF-related protein (CTRP) 9 is one of the adiponectin paralogs, and a genetic ablation of its receptor, AdipoR1, is known to cause retinal degeneration. The purpose of this study was to determine the role played by CTRP9 in the retina. Methods: The retinas of Ctrp9 gene knockout (KO) and wild type (WT) mice were examined by electroretinography (ERG), histology, RNA sequencing, and quantitative real-time PCR. Results: The amplitude of the photopic ERG elicited by the maximum stimulus intensity was smaller by 40% in the Ctrp9 KO mice than in WT mice at 8 weeks of age. However, the photopic ERGs was not reduced from 8 weeks to 6 months of age. The amplitudes of the scotopic ERGs were not reduced in the Ctrp9 KO mice at 8 weeks and 6 months of age. No distinct histological abnormalities were found in the retinal sections but the density of peanut agglutinin-stained cells in the retinal flat mount of KO mice was reduced to about 70% of that of WT mice. Genomewide RNA sequencing of the retina revealed the absence of the expression of CTRP9 in both KO and WT mice. RNA sequencing and quantitative real-time PCR analysis showed that the expressions of the transcripts of genes expressed in cones, Opn1sw, Opn1mw, Gnat2, and Cnga3, were reduced in the KO mice retina, however, the degree of expression of the transcripts in rods was not significantly reduced. Conclusions: CTRP9 is released ectopically from other tissues, and it regulates the number of cones in the mouse retinas.

DOI： 10.1167/iovs.63.5.14

Factor Xa inhibitor, edoxaban ameliorates renal injury after subtotal nephrectomy by reducing epithelial-mesenchymal transition and inflammatory response. International journal

Lixin Fang, Koji Ohashi, Hayato Ogawa, Naoya Otaka, Hiroshi Kawanishi, Tomonobu Takikawa, Yuta Ozaki, Kunihiko Takahara, Minako Tatsumi, Mikito Takefuji, Toyoaki Murohara, Noriyuki Ouchi

Physiological reports Vol. 10 ( 5 ) page： e15218 2022.3

Language：English Publishing type：Research paper (scientific journal)

Chronic kidney disease (CKD) is an increasing and life-threatening disease worldwide. Recent evidence indicates that blood coagulation factors promote renal dysfunction in CKD patients. Activated factor X (FXa) inhibitors are safe and first-line drugs for the prevention of thrombosis in patients with atrial fibrillation. Here, we investigated the therapeutic effects of edoxaban on CKD using the mouse 5/6 nephrectomy model. Eight-week-old wild-type mice were subjected to 5/6 nephrectomy surgery and randomly assigned to two groups, edoxaban or vehicle admixture diet. Edoxaban treatment led to reduction of urinary albumin excretion and plasma UN levels compared with vehicle group, which was accompanied with reduced glomerular cross-sectional area and cell number. Edoxaban treatment also attenuated fibrinogen positive area in the remnant kidneys after subtotal nephrectomy. Moreover, edoxaban treatment resulted in attenuated tubulointerstitial fibrosis after 5/6 nephrectomy, which was accompanied by reduced expression levels of epithelial-mesenchymal transition (EMT) markers, inflammatory mediators, and oxidative stress markers in the remnant kidneys. Treatment of cultured proximal tubular cells, HK-2 cells, with FXa protein led to increased expression levels of EMT markers, inflammatory mediators, and oxidative stress markers, which were abolished by pretreatment with edoxaban. Treatment of HK-2 cells with edoxaban attenuated FXa-stimulated phosphorylation levels of extracellular signal-regulated kinase (ERK) and NF-κB. Our findings indicate that edoxaban can improve renal injury after subtotal nephrectomy by reducing EMT and inflammatory response, suggesting that FXa inhibition could be a novel therapeutic target for CKD patients with atrial fibrillation.

DOI： 10.14814/phy2.15218

Neuron-derived neurotrophic factor protects against dexamethasone-induced skeletal muscle atrophy. International journal

Yuta Ozaki, Koji Ohashi, Naoya Otaka, Hayato Ogawa, Hiroshi Kawanishi, Tomonobu Takikawa, Lixin Fang, Minako Tatsumi, Mikito Takefuji, Takashi Enomoto, Mohamed Darwish, Yoko Iijima, Takatoshi Iijima, Toyoaki Murohara, Noriyuki Ouchi

Biochemical and biophysical research communications Vol. 593 page： 5 - 12 2022.2

Language：Japanese Publishing type：Research paper (scientific journal)

Skeletal muscle atrophy caused by various conditions including aging, nerve damage, and steroid administration, is a serious health problem worldwide. We recently reported that neuron-derived neurotrophic factor (NDNF) functions as a muscle-derived secreted factor, also known as myokine, which exerts protective actions on endothelial cell and cardiomyocyte function. Here, we investigated whether NDNF regulates skeletal muscle atrophy induced by steroid administration and sciatic denervation. NDNF-knockout (KO) mice and age-matched wild-type (WT) mice were subjected to continuous dexamethasone (DEX) treatment or sciatic denervation. NDNF-KO mice exhibited decreased gastrocnemius muscle weight and reduced cross sectional area of myocyte fiber after DEX treatment or sciatic denervation compared with WT mice. Administration of an adenoviral vector expressing NDNF (Ad-NDNF) or recombinant NDNF protein to gastrocnemius muscle of WT mice increased gastrocnemius muscle weight after DEX treatment. NDNF-KO mice showed increased expression of ubiquitin E3-ligases, including atrogin-1 and MuRF-1, in gastrocnemius muscle after DEX treatment, whereas Ad-NDNF reduced expression of atrogin-1 and MuRF-1 in gastrocnemius muscle of WT mice after DEX treatment. Pretreatment of cultured C2C12 myocytes with NDNF protein reversed reduced myotube diameter and increased expression of atrogin-1 and MuRF-1 after DEX stimulation. Treatment of C2C12 myocytes increased Akt phosphorylation. Pretreatment of C2C12 myotubes with the PI3-kinase/Akt inhibitor reversed NDNF-induced increase in myotube fiber diameter after DEX treatment. In conclusion, our findings indicated that NDNF prevents skeletal muscle atrophy in vivo and in vitro through reduction of ubiquitin E3-ligases expression, suggesting that NDNF could be a novel therapeutic target of muscle atrophy.

DOI： 10.1016/j.bbrc.2022.01.028

Corticotropin releasing hormone receptor 2 antagonist, RQ-00490721, for the prevention of pressure overload-induced cardiac dysfunction. International journal

Yu Mori, Ayako Tsuchihira, Tatsuya Yoshida, Satoya Yoshida, Akiyoshi Fujiuchi, Masashi Ohmi, Yumi Isogai, Teruhiro Sakaguchi, Shunsuke Eguchi, Takuma Tsuda, Katsuhiro Kato, Koji Ohashi, Noriyuki Ouchi, Hyi-Man Park, Toyoaki Murohara, Mikito Takefuji

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Vol. 146 page： 112566 - 112566 2022.2

Language：Japanese Publishing type：Research paper (scientific journal)

BACKGROUND: G protein-coupled receptors (GPCRs) regulate the pathological and physiological functions of the heart. GPCR antagonists are widely used in the treatment of chronic heart failure. Despite therapeutic advances in the treatments for cardiovascular diseases, heart failure is a major clinical health problem, with significant mortality and morbidity. Corticotropin releasing hormone receptor 2 (CRHR2) is highly expressed in cardiomyocytes, and cardiomyocyte-specific deletion of the genes encoding CRHR2 suppresses pressure overload-induced cardiac dysfunction. This suggests that the negative modulation of CRHR2 may prevent the progression of heart failure. However, there are no systemic drugs against CRHR2. FINDINGS: We developed a novel, oral, small molecule antagonist of CRHR2, RQ-00490721, to investigate the inhibition of CRHR2 as a potential therapeutic approach for the treatment of heart failure. In vitro, RQ-00490721 decreased CRHR2 agonist-induced 3', 5'-cyclic adenosine monophosphate (cAMP) production. In vivo, RQ-00490721 showed sufficient oral absorption and better distribution to peripheral organs than to the central nervous system. Oral administration of RQ-00490721 inhibited the CRHR2 agonist-induced phosphorylation of cAMP-response element binding protein (CREB) in the heart, which regulates a transcription activator involved in heart failure. RQ-00490721 administration was not found to affect basal heart function in mice but protected them from pressure overload-induced cardiac dysfunction. INTERPRETATION: Our results suggest that RQ-00490721 is a promising agent for use in the treatment of chronic heart failure.

DOI： 10.1016/j.biopha.2021.112566

LPL/AQP7/GPD2 promotes glycerol metabolism under hypoxia and prevents cardiac dysfunction during ischemia

Sohta Ishihama, Satoya Yoshida, Tatsuya Yoshida, Yu Mori, Noriyuki Ouchi, Shunsuke Eguchi, Teruhiro Sakaguchi, Takuma Tsuda, Katsuhiro Kato, Yuuki Shimizu, Koji Ohashi, Takahiro Okumura, Yasuko K. Bando, Hiroaki Yagyu, Nina Wettschureck, Naoto Kubota, Stefan Offermanns, Takashi Kadowaki, Toyoaki Murohara, Mikito Takefuji

The FASEB Journal Vol. 35 ( 12 ) page： e22048 2021.12

Adverse Effect of Circadian Rhythm Disorder on Reparative Angiogenesis in Hind Limb Ischemia Reviewed

Tsuzuki Kazuhito, Shimizu Yuuki, Suzuki Junya, Pu Zhongyue, Yamaguchi Shukuro, Fujikawa Yusuke, Kato Katsuhiro, Ohashi Koji, Takefuji Mikito, Bando Yasuko K., Ouchi Noriyuki, Calvert John W., Shibata Rei, Murohara Toyoaki

JOURNAL OF THE AMERICAN HEART ASSOCIATION Vol. 10 ( 16 ) page： e020896 2021.8

Prognostic impact of transcardiac gradient of follistatin-like 1 reflecting hemodynamics in patients with dilated cardiomyopathy. Reviewed

Oishi H, Okumura T, Ohashi K, Kimura Y, Kazama S, Shibata N, Arao Y, Kato H, Kuwayama T, Yamaguchi S, Tatsumi M, Kondo T, Hiraiwa H, Morimoto R, Takefuji M, Ouchi N, Murohara T

Journal of cardiology 2021.7

Important Role of Concomitant Lymphangiogenesis for Reparative Angiogenesis in Hindlimb Ischemia Reviewed

Pu Zhongyue, Shimizu Yuuki, Tsuzuki Kazuhito, Suzuki Junya, Hayashida Ryo, Kondo Kazuhisa, Fujikawa Yusuke, Unno Kazumasa, Ohashi Koji, Takefuji Mikito, Bando Yasuko K., Ouchi Noriyuki, Calvert John W., Shibata Rei, Murohara Toyoaki

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Vol. 41 ( 6 ) page： 2006 - 2018 2021.6

Omentin attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein-E knockout mice. Reviewed

Fang L, Ohashi K, Otaka N, Ogawa H, Hiramatsu-Ito M, Kawanishi H, Bando YK, Shibata R, Shimizu Y, Kato K, Takikawa T, Ozaki Y, Takefuji M, Murohara T, Ouchi N

Cardiovascular research 2021.5

Adipolin/C1q/Tnf-related protein 12 prevents adverse cardiac remodeling after myocardial infarction Reviewed

Takikawa Tomonobu, Ohashi Koji, Ogawa Hayato, Otaka Naoya, Kawanishi Hiroshi, Fang Lixin, Ozaki Yuta, Eguchi Shunsuke, Tatsumi Minako, Takefuji Mikito, Murohara Toyoaki, Ouchi Noriyuki

PLOS ONE Vol. 15 ( 12 ) page： e0243483 2020.12

C1q/TNF-Related Protein 9 Promotes Revascularization in Response to Ischemia via an eNOS-Dependent Manner Reviewed

Shukuro Yamaguchi, Rei Shibata, Koji Ohashi, Takashi Enomoto, Hayato Ogawa, Naoya Otaka, Mizuho Hiramatsu-Ito, Tomohiro Masutomi, Hiroshi Kawanishi, Toyoaki Murohara, Noriyuki Ouchi

Frontiers in Pharmacology Vol. 11 page： 1313 2020.8

Can Pharmacological Ischemic Preconditioning Affect Myocardial Ischemic Injury? Reviewed

Koji Ohashi, Noriyuki Ouchi, Toyoaki Murohara

Circulation Journal Vol. 84 ( 6 ) page： 891 - 893 2020.6

Adipolin/CTRP12 protects against pathological vascular remodelling through suppression of smooth muscle cell growth and macrophage inflammatory response Reviewed

Hayato Ogawa, Koji Ohashi, Masanori Ito, Rei Shibata, Noriyoshi Kanemura, Daisuke Yuasa, Takahiro Kambara, Kazuhiro Matsuo, Satoko Hayakawa, Mizuho Hiramatsu-Ito, Naoya Otaka, Hiroshi Kawanishi, Shukuro Yamaguchi, Takashi Enomoto, Takaya Abe, Mari Kaneko, Mikito Takefuji, Toyoaki Murohara, Noriyuki Ouchi

Cardiovascular Research Vol. 116 ( 1 ) page： 237 - 249 2020.1

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Oxford University Press (OUP)

<title>Abstract</title>
<sec>
<title>Aims</title>
Secreted factors produced by adipose tissue are involved in the pathogenesis of cardiovascular disease. We previously identified adipolin, also known as C1q/TNF-related protein 12, as an insulin-sensitizing adipokine. However, the role of adipolin in vascular disease remains unknown. Here, we investigated whether adipolin modulates pathological vascular remodelling.

</sec>
<sec>
<title>Methods and results</title>
Adipolin-knockout (APL-KO) and wild-type (WT) mice were subjected to wire-induced injury of the femoral artery. APL-KO mice showed increased neointimal thickening after vascular injury compared with WT mice, which was accompanied by an enhanced inflammatory response and vascular cell proliferation in injured arteries. Adipolin deficiency also led to a reduction in transforming growth factor-β (TGF-β) 1 protein levels in injured arteries. Treatment of cultured macrophages with adipolin protein led to a reduction in lipopolysaccharide-stimulated expression of inflammatory mediators, including tumour necrosis factor (TNF)-α, interleukin (IL) 6, and monocyte chemotactic protein (MCP)-1. These effects were reversed by inhibition of TGF-β receptor II (TGF-βRII)/Smad2 signalling. Adipolin also reduced platelet-derived growth factor (PDGF)-BB-stimulated proliferation of vascular smooth muscle cells (VSMCs) through a TGF-βRII/Smad2-dependent pathway. Furthermore, adipolin treatment significantly increased TGF-β1 concentration in media from cultured VSMCs and macrophages.

</sec>
<sec>
<title>Conclusion</title>
These data indicate that adipolin protects against the development of pathological vascular remodelling by attenuating macrophage inflammatory responses and VSMC proliferation.

</sec>

DOI： 10.1093/cvr/cvz074

Other Link： http://academic.oup.com/cardiovascres/article-pdf/116/1/237/31555893/cvz074.pdf

Protein Kinase N Promotes Stress-Induced Cardiac Dysfunction Through Phosphorylation of Myocardin-Related Transcription Factor A and Disruption of its Interaction with Actin. Reviewed

Sakaguchi T, Takefuji M, Wettschureck N, Hamaguchi T, Amano M, Kato K, Tsuda T, Eguchi S, Ishihama S, Mori Y, Yura Y, Yoshida T, Unno K, Okumura T, Ishii H, Shimizu Y, Bando YK, Ohashi K, Ouchi N, Enomoto A, Offermanns S, Kaibuchi K, Murohara T

Circulation Vol. 140 ( 21 ) page： 1737 - 1752 2019.11

Cardiomyocytes capture stem cell-derived, anti-apoptotic microRNA-214 via clathrin-mediated endocytosis in acute myocardial infarction. Reviewed

Eguchi S, Takefuji M, Sakaguchi T, Ishihama S, Mori Y, Tsuda T, Takikawa T, Yoshida T, Ohashi K, Shimizu Y, Hayashida R, Kondo K, Bando YK, Ouchi N, Murohara T

The Journal of biological chemistry Vol. 294 ( 31 ) page： 11665 - 11674 2019.8

Associations among circulating levels of follistatin-like 1, clinical parameters, and cardiovascular events in patients undergoing elective percutaneous coronary intervention with drug-eluting stents. Reviewed

Aikawa T, Shimada K, Miyauchi K, Miyazaki T, Sai E, Ouchi S, Kadoguchi T, Kunimoto M, Joki Y, Dohi T, Okazaki S, Isoda K, Ohashi K, Murohara T, Ouchi N, Daida H

PloS one Vol. 14 ( 4 ) page： e0216297 2019.4

Myonectin Is an Exercise-Induced Myokine That Protects the Heart From Ischemia-Reperfusion Injury Reviewed

Otaka Naoya, Shibata Rei, Ohashi Koji, Uemura Yusuke, Kambara Takahiro, Enomoto Takashi, Ogawa Hayato, Ito Masanori, Kawanishi Hiroshi, Maruyama Sonomi, Joki Yusuke, Fujikawa Yusuke, Narita Shingo, Unno Kazumasa, Kawamoto Yoshiyuki, Murate Takashi, Murohara Toyoaki, Ouchi Noriyuki

CIRCULATION RESEARCH Vol. 123 ( 12 ) page： 1326-1338 2018.12

Role of Adipokines in Cardiovascular Disease Reviewed

Lau Wayne Bond, Ohashi Koji, Wang Yajing, Ogawa Hayato, Murohara Toyoaki, Ma Xin-Liang, Ouchi Noriyuki

CIRCULATION JOURNAL Vol. 81 ( 7 ) page： 920-928 2017.7

C1q/TNF-related protein 1 prevents neointimal formation after arterial injury Reviewed

Kanemura Noriyoshi, Shibata Rei, Ohashi Koji, Ogawa Hayato, Hiramatsu-Ito Mizuho, Enomoto Takashi, Yuasa Daisuke, Ito Masanori, Hayakawa Satoko, Otaka Naoya, Murohara Toyoaki, Ouchi Noriyuki

ATHEROSCLEROSIS Vol. 257 page： 138-145 2017.2

The role of adipokines in cardiovascular disease Reviewed

Shibata Rei, Ouchi Noriyuki, Ohashi Koji, Murohara Toyoaki

JOURNAL OF CARDIOLOGY Vol. 70 ( 3-4 ) page： 329-334 2017

Protective Roles of Adipocytokines and Myokines in Cardiovascular Disease Reviewed

Noriyuki Ouchi, Koji Ohashi, Rei Shibata, Toyoaki Murohara

CIRCULATION JOURNAL Vol. 80 ( 10 ) page： 2073 - 2080 2016.10

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：JAPANESE CIRCULATION SOC

Obesity is a major risk factor for progression of cardiovascular disease. Adipose tissue is recognized as an endocrine organ producing various secretory molecules, also known as adipocytokines, and dysregulated production of adipocytokines participates in the pathogenesis of obesity complications, including metabolic dysfunction and cardiovascular disorders. Recent evidence indicates that skeletal muscle also functions as an endocrine organ capable of secreting a number of bioactive substances, also referred to as myokines. Several myokines are involved in metabolic and cardiovascular regulation. This review will discuss the clinical and experimental studies that have investigated the protective role of several adipocytokines and myokines in cardiovascular diseases.

DOI： 10.1253/circj.CJ-16-0663

Association of Circulating Follistatin-Like 1 Levels with Inflammatory and Oxidative Stress Markers in Healthy Men Reviewed

Satoko Hayakawa, Koji Ohashi, Rei Shibata, Ryotaro Takahashi, Naoya Otaka, Hayato Ogawa, Masanori Ito, Noriyoshi Kanemura, Mizuho Hiramatsu-Ito, Nobuo Ikeda, Toyoaki Murohara, Noriyuki Ouchi

PLOS ONE Vol. 11 ( 5 ) page： e0153619 2016.5

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Objectives
Follistatin-like 1 (Fstl1) is a circulating glycoprotein that plays a crucial role in cardiovascular diseases and inflammation-related disorders. We have shown that Fstl1 acts as an anti-inflammatory factor that protects against ischemic heart disease and chronic kidney disease. Here we examined whether plasma level of Fstl1 associates with markers of inflammation and oxidative stress in apparently healthy Japanese men.
Methods and Results
Plasma Fstl1 levels were measured by enzyme-linked immunosorbent assay. Circulating Fstl1 concentrations positively correlated with levels of fasting immune-reactive insulin (FIRI), high-sensitive CRP (hsCRP) and derivatives of reactive oxidative metabolites (dROMs), an indicator of oxidative stress. The levels of hsCRP positively associated with Fstl1, body mass index (BMI), triglyceride, FIRI and dROMs levels. dROMs levels positively associated with Fstl1, Hemoglobin A1c and hsCRP levels. Multiple regression analysis with confounding factors revealed that Fstl1 levels, together with BMI and FIRI, correlated with hsCRP and that Fstl1 levels correlated with dROMs.
Conclusion
Our observations indicate that measurement of plasma Fstl1 levels can be valuable for assessment of pro-inflammatory and oxidative stress conditions.

DOI： 10.1371/journal.pone.0153619

Omentin attenuates atherosclerotic lesion formation in apolipoprotein E-deficient mice Reviewed

Mizuho Hiramatsu-Ito, Rei Shibata, Koji Ohashi, Yusuke Uemura, Noriyoshi Kanemura, Takahiro Kambara, Takashi Enomoto, Daisuke Yuasa, Kazuhiro Matsuo, Masanori Ito, Satoko Hayakawa, Hayato Ogawa, Naoya Otaka, Shinji Kihara, Toyoaki Murohara, Noriyuki Ouchi

CARDIOVASCULAR RESEARCH Vol. 110 ( 1 ) page： 107 - 117 2016.5

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Obesity is associated with the development of atherosclerosis. We previously demonstrated that omentin is a circulating adipokine that is downregulated in association with atherosclerotic diseases. Here, we examined the impact of omentin on the development of atherosclerosis with gain-of-function genetic manipulations and dissected its potential mechanism.
Apolipoprotein E-deficient (apoE-KO) mice were crossed with transgenic mice expressing the human omentin gene (OMT-Tg) mice in fat tissue to generate apoE-KO/OMT-Tg mice. ApoE-KO/OMT-Tg mice exhibited a significant reduction of the atherosclerotic areas in aortic sinus, compared with apoE-KO mice despite similar lipid levels. ApoE-KO/OMT-Tg mice also displayed significant decreases in macrophage accumulation and mRNA expression of proinflammatory mediators including tumour necrosis factor-alpha, interleukin-6, and monocyte chemotactic protein-1 in aorta when compared with apoE-KO mice. Treatment of human monocyte-derived macrophages with a physiological concentration of human omentin protein led to reduction of lipid droplets and cholesteryl ester content. Treatment with human omentin protein also reduced lipopolysaccharide-induced expression of proinflammatory genes in human macrophages. Treatment of human macrophages with omentin promoted the phosphorylation of Akt. Inhibition of Akt signalling abolished the anti-inflammatory actions of omentin in macrophages.
These data document for the first time that omentin reduces the development of atherosclerosis by reducing inflammatory response of macrophages through the Akt-dependent mechanisms.

DOI： 10.1093/cvr/cvv282

C1q/TNF-related protein-1 functions to protect against acute ischemic injury in the heart Reviewed

Daisuke Yuasa, Koji Ohashi, Rei Shibata, Naoki Mizutani, Yoshiyuki Kataoka, Takahiro Kambara, Yusuke Uemura, Kazuhiro Matsuo, Noriyoshi Kanemura, Satoko Hayakawa, Mizuho Hiramatsu-Ito, Masanori Ito, Hayato Ogawa, Takashi Murate, Toyoaki Murohara, Noriyuki Ouchi

FASEB JOURNAL Vol. 30 ( 3 ) page： 1065 - 1075 2016.3

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：FEDERATION AMER SOC EXP BIOL

Obesity is associated with an increased risk of cardiovascular disease. C1q/TNF-related protein (CTRP)-1 is a poorly characterized adipokine that is up-regulated in association with ischemic heart disease. We investigated the role of CTRP1 in myocardial ischemia injury. CTRP1-knockout mice showed increased myocardial infarct size, cardiomyocyte apoptosis, and proinflammatory gene expression after I/R compared with wild-type (WT) mice. In contrast, systemic delivery of CTRP1 attenuated myocardial damage after I/R in WT mice. Treatment of cardiomyocytes with CTRP1 led to reduction of hypoxia-reoxygenation-induced apoptosis and lipopolysaccharide-stimulated expression of proinflammatory cytokines, which was reversed by inhibition of sphingosine-1-phosphate (S1P) signaling. Treatment of cardiomyocytes with CTRP1 also resulted in the increased production of cAMP, which was blocked by suppression of S1P signaling. The antiapoptotic and anti-inflammatory actions of CTRP1 were cancelled by inhibition of adenylyl cyclase or knockdown of adiponectin receptor 1. Furthermore, blockade of S1P signaling reversed CTRP1-mediated inhibition of myocardial infarct size, apoptosis, and inflammation after I/R in vivo. These data indicate that CTRP1 protects against myocardial ischemic injury by reducing apoptosis and inflammatory response through activation of the S1P/cAMP signaling pathways in cardiomyocytes, suggesting that CTRP1 plays a crucial role in the pathogenesis of ischemic heart disease.

DOI： 10.1096/fj.15-279885

Role of a novel secreted factor omentin in cardiovascular disease Reviewed

Ouchi Noriyuki, Ohashi Koji, Shibata Rei, Murohara Toyoaki

JOURNAL OF PHARMACOLOGICAL SCIENCES Vol. 128 ( 3 ) page： S35 - S35 2015.7

C1q/Tumor Necrosis Factor-Related Protein 9 Protects against Acute Myocardial Injury through an Adiponectin Receptor I-AMPK-Dependent Mechanism Reviewed

Takahiro Kambara, Rei Shibata, Koji Ohashi, Kazuhiro Matsuo, Mizuho Hiramatsu-Ito, Takashi Enomoto, Daisuke Yuasa, Masanori Ito, Satoko Hayakawa, Hayato Ogawa, Tamar Aprahamian, Kenneth Walsh, Toyoaki Murohara, Noriyuki Ouchi

MOLECULAR AND CELLULAR BIOLOGY Vol. 35 ( 12 ) page： 2173 - 2185 2015.6

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：AMER SOC MICROBIOLOGY

Obesity is a risk factor for cardiovascular disease. C1q/tumor necrosis factor-related protein 9 (CTRP9) is an adipokine that is downregulated by obesity. We investigated the role of CTRP9 in cardiac injury with loss-of-function genetic manipulations and defined the receptor-mediated signaling pathway downstream of this adipokine. CTRP9-knockout (CTRP9-KO) mice at the age of 12 weeks were indistinguishable from wild-type (WT) mice under basal conditions. CTRP9-KO mice had exacerbated contractile left ventricle dysfunction following intraperitoneal injection of lipopolysaccharide (LPS) compared to WT mice. Administration of LPS to CTRP9-KO mice also resulted in increased expression of proinflammatory cytokines and oxidative stress markers in the heart compared to WT mice. Likewise, CTRP9-KO mice showed increased myocardial infarct size and elevated expression of inflammatory mediators in ischemic heart following ischemia and reperfusion compared to WT mice. Treatment of cardiac myocytes with CTRP9 protein led to suppression of LPS-induced expression of proinflammatory genes, which was reversed by blockade of AMPK or ablation of adiponectin receptor I (AdipoR1). Systemic delivery of CTRP9 attenuated LPS-induced cardiac dysfunction in WT mice but not in muscle-specific transgenic mice expressing dominant-negative mutant form of AMPK or in AdipoR1-knockout mice. CTRP9 protects against acute cardiac damage in response to pathological stimuli by suppressing inflammatory reactions through AdipoR1/AMPK-dependent mechanisms.

DOI： 10.1128/MCB.01518-14

FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism Reviewed

Yusuke Joki, Koji Ohashi, Daisuke Yuasa, Rei Shibata, Masanori Ito, Kazuhiro Matsuo, Takahiro Kambara, Yusuke Uemura, Satoko Hayakawa, Mizuho Hiramatsu-Ito, Noriyoshi Kanemura, Hayato Ogawa, Hiroyuki Daida, Toyoaki Murohara, Noriyuki Ouchi

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Vol. 459 ( 1 ) page： 124 - 130 2015.3

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Ischemic heart disease is one of the leading causes of death. Fibroblast growth factor 21 (FGF21) is a circulating factor with an anti-diabetic property. Skeletal muscle is an important source of FGF21 production. Here, we investigated whether skeletal muscle-derived FGF21 modulates cardiac remodeling in a murine model of myocardial infarction. Myocardial infarction was produced in C57BL/6J wild-type (WT) mice by the permanent ligation of the left anterior descending coronary artery (LAD). Adenoviral vectors expressing FGF21 (Ad-FGF21) or control beta-galactosidase were intramuscularly injected into mice at 3 days before permanent LAD ligation. Intramuscular injection of Ad-FGF21 increased plasma FGF21 levels in WT mice compared with control. Treatment of WT mice with Ad-FGF21 led to improvement of left ventricular systolic dysfunction and dilatation at 2 weeks after LAD ligation. Ad-FGF21 administration to WT mice also led to enhancement of capillary density in the infarct border zone, and reduction of myocyte apoptosis in the remote zone, which were accompanied by decreased expression of pro-inflammatory cytokines. Furthermore, treatment of WT mice with Ad-FGF21 increased plasma levels of adiponectin, which is a cardioprotective adipokine. The beneficial effects of Ad-FGF21 on cardiac dysfunction and inflammatory response after myocardial infarction were diminished in adiponectin-knockout mice. These data suggest that muscle-derived FGF21 ameliorates adverse cardiac remodeling after myocardial infarction, at least in part, through an adiponectin-dependent mechanism. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2015.02.081

Neuron-Derived Neurotrophic Factor Ameliorates Adverse Cardiac Remodeling After Experimental Myocardial Infarction. Reviewed

Joki Y, Ohashi K, Yuasa D, Shibata R, Kataoka Y, Kambara T, Uemura Y, Matsuo K, Hayakawa S, Hiramatsu-Ito M, Kanemura N, Ito M, Ogawa H, Daida H, Murohara T, Ouchi N.

Circulation: Heart Failure page： in press 2015.2

Omentin functions to attenuate cardiac hypertrophic response Reviewed

Kazuhiro Matsuo, Rei Shibata, Koji Ohashi, Takahiro Kambara, Yusuke Uemura, Mizuho Hiramatsu-Ito, Takashi Enomoto, Daisuke Yuasa, Yusuke Joki, Masanori Ito, Satoko Hayakawa, Hayato Ogawa, Shinji Kihara, Toyoaki Murohara, Noriyuki Ouchi

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY Vol. 79 page： 195 - 202 2015.2

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD

Cardiac hypertrophy occurs in many obesity-related conditions. Omentin is an adipose-derived plasma protein that is downregulated under obese conditions. Here, we investigated whether omentin modulates cardiac hypertrophic responses in vivo and in vitro. Systemic administration of an adenoviral vector expressing human omentin (Ad-OMT) to wild-type (WT) mice led to the attenuation of cardiac hypertrophy, fibrosis and ERK phosphorylation induced by transverse aortic constriction (TAC) or angiotensin II infusion. In cultured cardiomyocytes, stimulation with phenylephrine (PE) led to an increase in myocyte size, which was prevented by pretreatment with human omentin protein. Pretreatment of cardiomyocytes with omentin protein also reduced ERK phosphorylation in response to PE stimulation. Ad-OMT enhanced phosphorylation of AMP-activated protein kinase (AMPK) in the heart of WT mice after TAC operation. Blockade of AMPK activation by transduction with dominant-negative mutant forms of AMPK reversed the inhibitory effect of omentin on myocyte hypertrophy and ERK phosphorylation following PE stimulation. Moreover, fat-specific transgenic mice expressing human omentin showed reduced cardiac hypertrophy and ERK phosphorylation following TAC surgery compared to littermate controls. These data suggest that omentin functions to attenuate the pathological process of myocardial hypertrophy via the activation of AMPK in the heart, suggesting that omentin may represent a target molecule for the treatment of cardiac hypertrophy. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.yjmcc.2014.11.019

Adipose-derived protein omentin prevents neointimal formation after arterial injury Reviewed

Yusuke Uemura, Rei Shibata, Noriyoshi Kanemura, Koji Ohashi, Takahiro Kambara, Mizuho Hiramatsu-Ito, Takashi Enomoto, Daisuke Yuasa, Yusuke Joki, Kazuhiro Matsuo, Masanori Ito, Satoko Hayakawa, Hayato Ogawa, Toyoaki Murohara, Noriyuki Ouchi

FASEB JOURNAL Vol. 29 ( 1 ) page： 141 - 151 2015.1

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：FEDERATION AMER SOC EXP BIOL

Obesity is highly linked with the development of vascular diseases. Omentin is a circulating adipokine that is downregulated in patients with cardiovascular diseases. In this study, we investigated the role of omentin in regulation of vascular remodeling in response to injury. Wild-type (WT) mice were treated intravenously with adenoviral vectors encoding human omentin (Ad-OMT) or control beta-gal and subjected to arterial wire injury. Ad-OMT treatment reduced the neointimal thickening and the frequencies of bromodeoxyuridine-positive proliferating cells in injured arteries. Treatment of vascular smooth muscle cells (VSMCs) with human omentin protein at a physiologic concentration led to suppression of growth and ERK phosphorylation after stimulation with various growth factors. Omentin stimulated AMPK signaling in VSMCs, and blockade of AMPK reversed omentin-mediated inhibition of VSMC growth and ERK phosphorylation. Furthermore, fat-specific human omentin transgenic (OMT-TG) mice exhibited reduced neointimal thickening and vascular cell growth following vascular injury. AMPK activation was enhanced in injured arteries in OMT-TG mice, and administration of AMPK inhibitor reversed the reduction of neointimal hyperplasia in OMT-TG mice. These data indicate that omentin attenuates neointimal formation after arterial injury and suppresses VSMC growth through AMPK-dependent mechanisms. Thus, omentin can represent a novel target molecule for the prevention of vascular disorders.

DOI： 10.1096/fj.14-258129

Adiponectin as a Target in Obesity-related Inflammatory State Reviewed

Koji Ohashi, Daisuke Yuasa, Rei Shibata, Toyoaki Murohara, Noriyuki Ouchi

ENDOCRINE METABOLIC & IMMUNE DISORDERS-DRUG TARGETS Vol. 15 ( 2 ) page： 145 - 150 2015

Language：English Publishing type：Research paper (scientific journal) Publisher：BENTHAM SCIENCE PUBL LTD

Accumulating evidence indicates that low grade inflammation is closely associated with obesity-related disorders including type 2 diabetes, hypertension and atherosclerosis. Adiponectin is a fat-derived plasma protein with anti-inflammatory functions. Circulating levels of adiponectin are decreased in obese states, and these conditions are broadly associated with various obesity-related diseases. Furthermore, adiponectin has direct protective functions against cardiovascular disease, cerebrovascular disease, non-alcoholic steatohepatitis (NASH) and chronic kidney disease (CKD). In this review, we will focus on the protective functions of adiponectin against these obesity-related diseases from the view point of its anti-inflammatory properties.

The potential of adipokines as therapeutic agents for cardiovascular disease Reviewed

Rei Shibata, Koji Ohashi, Toyoaki Murohara, Noriyuki Ouchi

CYTOKINE & GROWTH FACTOR REVIEWS Vol. 25 ( 4 ) page： 483 - 487 2014.8

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI LTD

Adipose tissue functions as an endocrine organ by producing bioactive secretory proteins, also known as adipokines, that can directly act on nearby or remote organs. Most of the adipokines are upregulated by obese conditions, and typically promote obese complications. In contrast, some adipokines, such as adiponectin, CTRP9 and omentin, are downregulated in obese states. These factors exert salutary actions on obesity-linked cardiovascular disorders. In this review, we focus on the significance of adiponectin, CTRP9 and omentin as therapeutic agents for cardiovascular disease. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.cytogfr.2014.07.005

Cardiac Myocyte-Derived Follistatin-Like 1 Prevents Renal Injury in a Subtotal Nephrectomy Model. Reviewed

Hayakawa S, Ohashi K, Shibata R, Kataoka Y, Miyabe M, Enomoto T, Joki Y, Shimizu Y, Kambara T, Uemura Y, Yuasa D, Ogawa H, Matsuo K, Hiramatsu-Ito M, van den Hoff MJ, Walsh K, Murohara T, Ouchi N.

Journal of American Society of Nephrology page： in press 2014.7

Role of anti-inflammatory adipokines in obesity-related diseases. Reviewed

Ohashi K, Shibata R, Murohara T, Ouchi N.

Trend Endocrinology and Metabolism 2014.7

Muscle-derived follistatin-like 1 functions to reduce neointimal formation after vascular injury. Reviewed

Miyabe M, Ohashi K, Shibata R, Uemura Y, Ogura Y, Yuasa D, Kambara T, Kataoka Y, Yamamoto T, Matsuo K, Joki Y, Enomoto T, Hayakawa S, Hiramatsu-Ito M, Ito M, Van Den Hoff MJ, Walsh K, Murohara T, Ouchi N.

Cardiovascular Research 2014.7

Omentin prevents myocardial ischemic injury through AMP-activated protein kinase- and Akt-dependent mechanisms. Reviewed

Kataoka Y, Shibata R, Ohashi K, Kambara T, Enomoto T, Uemura Y, Ogura Y, Yuasa D, Matsuo K, Nagata T, Oba T, Yasukawa H, Numaguchi Y, Sone T, Murohara T, Ouchi N.

Journal of American College of Cardiology 2014.6

Association of circulating C1q/TNF-related protein 1 levels with coronary artery disease in men. Reviewed

Yuasa D, Ohashi K, Shibata R, Takeshita K, Kikuchi R, Takahashi R, Kataoka Y, Miyabe M, Joki Y, Kambara T, Uemura Y, Matsuo K, Hayakawa S, Hiramatsu-Ito M, Ito M, Ikeda N, Murohara T, Ouchi N.

PLoS One 2014.6

Association of Circulating C1q/TNF-Related Protein 1 Levels with Coronary Artery Disease in Men Reviewed

Daisuke Yuasa, Koji Ohashi, Rei Shibata, Kyosuke Takeshita, Ryosuke Kikuchi, Ryotaro Takahashi, Yoshiyuki Kataoka, Megumi Miyabe, Yusuke Joki, Takahiro Kambara, Yusuke Uemura, Kazuhiro Matsuo, Satoko Hayakawa, Mizuho Hiramatsu-Ito, Masanori Ito, Nobuo Ikeda, Toyoaki Murohara, Noriyuki Ouchi

PLOS ONE Vol. 9 ( 6 ) page： e99846 2014.6

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Objective: Obesity is a major risk factor for cardiovascular disease. Recent evidence demonstrates that dysregulation of fat-derived hormones, also known as adipokines, is linked with the pathogenesis of obesity-related disorders including coronary artery disease (CAD). Here, we investigated whether circulating level of an adipokine C1q/TNF-related protein (CTRP) 1 is associated with the prevalence of CAD.
Methods and Results: Consecutive 76 male CAD patients were enrolled from inpatients that underwent coronary angiography. Sixty four healthy male subjects served as controls. Plasma CTRP1 concentration was determined by enzyme-linked immunosorbent assay. CTRP1 levels were correlated positively with systolic blood pressure (BP) and triglyceride levels, and negatively with HDL cholesterol levels in all subjects. Plasma levels of CTRP1 were significantly higher in CAD patients than in control subjects (CAD: 443.3 +/- 18.6 ng/ml, control: 307.8 +/- 21.5 ng/ml, p<0.001). Multiple logistic regression analysis with body mass index, systolic BP, glucose, total cholesterol, HDL cholesterol, triglyceride, adiponectin and CTRP1 revealed that CTRP1 levels, together with systolic BP and HDL cholesterol, correlated with CAD.
Conclusions: Our data indicate the close association of high CTRP1 levels with CAD prevalence, suggesting that CTRP1 represents a novel biomarker for CAD.

DOI： 10.1371/journal.pone.0099846

Neuron-derived neurotrophic factor functions as a novel modulator that enhances endothelial cell function and revascularization processes. Reviewed

Ohashi K, Enomoto T, Joki Y, Shibata R, Ogura Y, Kataoka Y, Shimizu Y, Kambara T, Uemura Y, Yuasa D, Matsuo K, Hayakawa S, Hiramatsu-Ito M, Murohara T, Ouchi N.

The Journal of Biological Chemistry 2014.5

Adiponectin Ameliorates Endotoxin-Induced Acute Cardiac Injury Reviewed

Yoshio Watanabe, Rei Shibata, Noriyuki Ouchi, Takahiro Kambara, Koji Ohashi, Li Jie, Yoko Inoue, Toyoaki Murohara, Kimihiro Komori

BIOMED RESEARCH INTERNATIONAL Vol. 2014 page： 382035 2014

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：HINDAWI PUBLISHING CORPORATION

Background. Obesity is a risk factor for cardiovascular disease. Increasing evidence suggests that reduced levels of the adipocyte-derived plasma protein adiponectin are associated with an increased cardiovascular risk. Here, we examined the effects of adiponectin on lipopolysaccharide- (LPS-) induced acute cardiac injury in vivo. Methods and Results. A single dose of LPS (10mg/kg) was intraperitoneally injected into wild-type (WT) and adiponectin-knockout (APN-KO) mice. Following LPS administration, APN-KO mice had exacerbation of left ventricular (LV) systolic dysfunction compared with WT mice. Administration of LPS to WT and APN-KO mice led to an increased expression of inflammatory cytokines including TNF-alpha and IL-6 in the heart, but the magnitude of this induction was greater in APN-KO mice compared to WT mice. Systemic delivery of an adenoviral vector expressing adiponectin (Ad-APN) improved LPS-induced LV dysfunction in APN-KO mice, and this effect was accompanied by the reduced expression of TNF-alpha and IL-6 in the heart. Administration of etanercept, a soluble TNF receptor abolished the reduced LV contractile function in response to LPS in APN-KO mice. Conclusion. These results suggest that adiponectin protects against LPS-induced acute cardiac injury by suppressing cardiac inflammatory responses, and could represent a potential therapeutic target in sepsis-associated myocardial dysfunction.

DOI： 10.1155/2014/382035

Transcriptional Regulation of an Insulin-Sensitizing Adipokine Adipolin/CTRP12 in Adipocytes by Kruppel-Like Factor 15 Reviewed

Takashi Enomoto, Koji Ohashi, Rei Shibata, Takahiro Kambara, Yusuke Uemura, Daisuke Yuasa, Yoshiyuki Kataoka, Megumi Miyabe, Kazuhiro Matsuo, Yusuke Joki, Satoko Hayakawa, Mizuho Hiramatsu-Ito, Masanori Ito, Toyoaki Murohara, Noriyuki Ouchi

PLOS ONE Vol. 8 ( 12 ) page： e83183 2013.12

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Obese states characterized by chronic inflammation are closely linked to the development of metabolic dysfunction. We identified adipolin/CTRP12 as an insulin-sensitizing and anti-inflammatory adipokine. Although obese conditions down-regulate adipolin expression, its molecular mechanism is largely unknown. Here we show that the transcriptional regulator Kruppel-like factor (KLF) 15 is involved in the regulation of adipolin expression in adipocytes. White adipose tissue from diet-induced obese (DIO) mice showed decreased expression of KLF9 and KLF15 among several KLFs, which was accompanied by reduced expression of adipolin. In cultured 3T3L1 adipocytes, treatment with TNF alpha significantly reduced the mRNA levels of KLF9, KLF15 and adipolin. Adenovirus-mediated overexpression of KLF15 but not KLF9 reversed TNF alpha-induced reduction of adipolin expression in adipocytes. Conversely, gene targeting ablation of KLF15 attenuated adipolin expression in adipocytes. Expression of KLF15 but not KLF9 enhanced the promoter activity of adipolin in HEK293 cells. Pretreatment of 3T3L1 adipocytes with the JNK inhibitor SP600125, but not p38 MAPK inhibitor SB203580 blocked the inhibitory effects of TNF alpha on adipolin and KLF15 expression. These data suggest that adipose inflammation under conditions of obesity suppresses adipolin expression via JNK-dependent down-regulation of KLF15 in adipocytes.

DOI： 10.1371/journal.pone.0083183

Adiponectin-Mediated Modulation of Lymphatic Vessel Formation and Lymphedema Reviewed

Yuuki Shimizu, Rei Shibata, Masakazu Ishii, Koji Ohashi, Takahiro Kambara, Yusuke Uemura, Daisuke Yuasa, Yoshiyuki Kataoka, Shinji Kihara, Toyoaki Murohara, Noriyuki Ouchi

JOURNAL OF THE AMERICAN HEART ASSOCIATION Vol. 2 ( 5 ) page： e000438 2013.10

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Background-Obesity is linked with an increased risk of lymphedema, which is a serious clinical problem. Adiponectin is a circulating adipokine that is down-regulated in obese states. We investigated the effects of adiponectin on lymphatic vessel formation in a model of lymphedema and dissected its mechanisms.
Methods and Results-A mouse model of lymphedema was created via ablation of tail surface lymphatic network. Adiponectin-knockout mice showed the greater diameter of the injured tail compared with wild-type mice, which was associated with lower numbers of lymphatic endothelial cells (LECs). Systemic delivery of adiponectin reduced the thickness of the injured tail and enhanced LEC formation in wild-type and adiponectin-knockout mice. Adiponectin administration also improved the edema of injured tails in obese KKAy mice. Treatment with adiponectin protein stimulated the differentiation of human LECs into tubelike structures and increased LEC viability. Adiponectin treatment promoted the phosphorylation of AMP-activated protein kinase (AMPK), Akt, and endothelial nitric oxide synthase n LECs. Blockade of AMPK or Akt activity abolished adiponectin-stimulated increase in LEC differentiation and viability and endothelial nitric oxide synthase phosphorylation. Inhibition of AMPK activation also suppressed adiponectin-induced Akt phosphorylation in LECs. In contrast, inactivation of Akt signaling had no effects on adiponectin-mediated AMPK phosphorylation in LECs. Furthermore, adiponectin administration did not affect the thickening of the damaged tail in endothelial nitric oxide synthase-knockout mice.
Conclusions-Adiponectin can promote lymphatic vessel formation via activation of AMPK/Akt/endothelial nitric oxide synthase signaling within LECs, thereby leading to amelioration of lymphedema.

DOI： 10.1161/JAHA.113.000438

Role of Adipocytokines in Regulation of Revascularization Responses

Ouchi Noriyuki, Ohashi Koji, Shibata Rei, Murohara Toyoaki

JOURNAL OF CARDIAC FAILURE Vol. 19 ( 10 ) page： S120 - S120 2013.10

Adipose-derived factor CTRP9 attenuates vascular smooth muscle cell proliferation and neointimal formation Reviewed

Yusuke Uemura, Rei Shibata, Koji Ohashi, Takashi Enomoto, Takahiro Kambara, Takashi Yamamoto, Yasuhiro Ogura, Daisuke Yuasa, Yusuke Joki, Kazuhiro Matsuo, Megumi Miyabe, Yoshiyuki Kataoka, Toyoaki Murohara, Noriyuki Ouchi

FASEB Journal Vol. 27 ( 1 ) page： 25 - 33 2013.1

Language：English Publishing type：Research paper (scientific journal)

Obesity is closely associated with the progression of vascular disorders, including atherosclerosis and postangioplasty restenosis. C1q/TNF-related protein (CTRP) 9 is an adipocytokine that is down-regulated in obese mice. Here we investigated whether CTRP9 modulates neointimal hyperplasia and vascular smooth muscle cell (VSMC) proliferation in vivo and in vitro. Left femoral arteries of wild-type (WT) mice were injured by a steel wire. An adenoviral vector expressing CTRP9 (Ad-CTRP9) or β-galactosidase as a control was intravenously injected into WT mice 3 d before vascular injury. Delivery of Ad-CTRP9 significantly attenuated the neointimal thickening and the number of bromodeoxyuridine-positive proliferating cells in the injured arteries compared with that of control. Treatment of VSMCs with CTRP9 protein attenuated the proliferative and chemotactic activities induced by growth factors including platelet-derived growth factor (PDGF)-BB, and suppressed PDGF-BB-stimulated phosphorylation of ERK. CTRP9 treatment dose-dependently increased cAMP levels in VSMCs. Blockade of cAMP-PKA pathway reversed the inhibitory effect of CTRP9 on DNA synthesis and ERK phosphorylation in response to PDGF-BB. The present data indicate that CTRP9 functions to attenuate neointimal formation following vascular injury through its ability to inhibit VSMC growth via cAMP-dependent mechanism, suggesting that the therapeutic approaches to enhance CTRP9 production could be valuable for prevention of vascular restenosis after angioplasty. © FASEB.

DOI： 10.1096/fj.12-213744

Regulation of adipolin/CTRP12 cleavage by obesity Reviewed

Takashi Enomoto, Rei Shibata, Koji Ohashi, Takahiro Kambara, Yoshiyuki Kataoka, Yusuke Uemura, Daisuke Yuasa, Toyoaki Murohara, Noriyuki Ouchi

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Vol. 428 ( 1 ) page： 155 - 159 2012.11

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Obesity is highly associated with the development of insulin resistance and type 2 diabetes. Recently we found that adipolin/CRTP12 is an adipocytokine that exerts beneficial actions on glucose metabolism. Here we investigated the regulation of circulating adipolin under conditions of obesity and assessed its potential mechanisms. Both full and cleaved forms of adipolin were observed in mouse plasma. Diet-induced obese (DIO) mice showed a significant reduction of plasma levels of full and total (full and cleaved) adipolin compared with control mice, resulting in an increase in the ratio of cleaved to full isoform. In vitro gene transfection studies using HEK293 cells revealed that a deletion mutant of adipolin gene (Delta aa90-93) caused a reduction of cleaved production of adipolin in media. A bioinformatics analysis of adipolin amino acid sequence indicated the potential involvement of the family of proprotein convertases (PCs) in cleavage of adipolin. Treatment of 3T3-L1 adipocytes with an inhibitor for PCs abolished the expression of cleaved adipolin form in the media. The expression of furin, the member of PCs, was increased in adipose tissue of DID mice. Furin expression was also increased in cultured adipocytes by treatment with an inducer of inflammation. These data suggest that obesity states facilitate the cleavage of adipolin presumably through upregulation of furin in adipose tissue. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2012.10.031

Therapeutic impact of follistatin-like 1 on myocardial ischemic injury in preclinical models. Reviewed

Ogura Y, Ouchi N, Ohashi K, Shibata R, Kataoka Y, Kambara T, Kito T, Maruyama S, Yuasa D, Matsuo K, Enomoto T, Uemura Y, Miyabe M, Ishii M, Yamamoto T, Shimizu Y, Walsh K, Murohara T.

Circulation 2012.10

Omentin as a novel biomarker of metabolic risk factors Reviewed

Rei Shibata, Noriyuki Ouchi, Ryotaro Takahashi, Yuya Terakura, Koji Ohashi, Nobuo Ikeda, Akiko Higuchi, Hiroko Terasaki, Shinji Kihara, Toyoaki Murohara

DIABETOLOGY & METABOLIC SYNDROME Vol. 4 ( 1 ) page： 37 2012.7

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: Omentin is an adipocytokine that is abundantly expressed in visceral fat tissue. We investigated the association of omentin with the number of metabolic risk factors.
Finding: The study population comprised 201 Japanese men who underwent annual health checkups. Plasma omentin levels were determined by enzyme-linked immunosorbent assay. We divided the subjects into 4 groups according to omentin levels. A reduction of plasma omentin levels significantly correlated with an increase in the mean number of metabolic risk factors such as increased waist circumference, dyslipidemia, high blood pressure and glucose intolerance.
Conclusions: Circulating omentin levels negatively correlated with the multiplicity of metabolic risk factors, suggesting that omentin acts as a biomarker of metabolic disorders.

DOI： 10.1186/1758-5996-4-37

Anti-inflammatory and anti-atherogenic properties of adiponectin. Reviewed

Ohashi K, Ouchi N, Matsuzawa Y.

Biochimie 2012.6

CTRP9 protein protects against myocardial injury following ischemia-reperfusion through AMP-activated protein kinase (AMPK)-dependent mechanism. Reviewed

Kambara T, Ohashi K, Shibata R, Ogura Y, Maruyama S, Enomoto T, Uemura Y, Shimizu Y, Yuasa D, Matsuo K, Miyabe M, Kataoka Y, Murohara T, Ouchi N.

The Journal of Biological Chemistry 2012.6

Fat-derived Factor Omentin Stimulates Endothelial Cell Function and Ischemia-induced Revascularization via Endothelial Nitric Oxide Synthase-dependent Mechanism Reviewed

Sonomi Maruyama, Rei Shibata, Ryosuke Kikuchi, Yasuhiro Izumiya, Taku Rokutanda, Satoshi Araki, Yoshiyuki Kataoka, Koji Ohashi, Hiroyuki Daida, Shinji Kihara, Hisao Ogawa, Toyoaki Murohara, Noriyuki Ouchi

JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 287 ( 1 ) page： 408 - 417 2012.1

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Obesity-related diseases are associated with vascular dysfunction and impaired revascularization. Omentin is a fat-derived secreted protein, which is down-regulated in association with obese complications. Here, we investigated whether omentin modulates endothelial cell function and revascularization processes in vitro and in vivo. Systemic delivery of an adenoviral vector expressing omentin (Ad-omentin) enhanced blood flow recovery and capillary density in ischemic limbs of wild-type mice in vivo, which were accompanied by increased phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). In cultured human umbilical vein endothelial cells (HUVECs), a physiological concentration of recombinant omentin protein increased differentiation into vascular-like structures and decreased apoptotic activity under conditions of serum starvation. Treatment with omentin protein stimulated the phosphorylation of Akt and eNOS in HUVECs. Inhibition of Akt signaling by treatment with dominant-negative Akt or LY294002 blocked the stimulatory effects of omentin on differentiation and survival of HUVECs and reversed omentin-stimulated eNOS phosphorylation. Pretreatment with the NOS inhibitor also reduced the omentin-induced increase in HUVEC differentiation and survival. Omentin protein also stimulated the phosphorylation of AMP-activated protein kinase in HUVECs. Transduction with dominant-negative AMP-activated protein kinase diminished omentin-induced phosphorylation of Akt and omentin-stimulated increase in HUVEC differentiation and survival. Of importance, in contrast to wild-type mice, systemic administration of Ad-omentin did not affect blood flow in ischemic muscle in eNOS-deficient mice in vivo. These data indicate that omentin promotes endothelial cell function and revascularization in response to ischemia through its ability to stimulate an Akt-eNOS signaling pathway.

DOI： 10.1074/jbc.M111.261818

Adipocytokines and obesity-linked disorders Reviewed

Noriyuki Ouchi, Koji Ohashi, Rei Shibata, Toyoaki Murohara

Nagoya Journal of Medical Science Vol. 74 ( 1-2 ) page： 19 - 30 2012

Language：English Publishing type：Research paper (scientific journal)

Obesity is closely associated with an increased risk for metabolic and cardiovascular diseases. Adipose tissue produces a number of secretory bioactive substances, also known as adipocytokines or adipokines, which directly affect adjacent or distant organs. Most adipocytokines are pro-inflammatory, thereby promoting the obesity-linked disorders. In contrast, there are a small number of adipocytokines that exhibit antiinflammatory properties. It is now recognized that dysregulated production or secretion of adipocytokines caused by adipocyte dysfunction leads to the development of obesity-linked complications. In this review, we focus on the functional role of several adipocytokines in metabolic and cardiovascular diseases.

Circulating omentin is associated with coronary artery disease in men Reviewed

Rei Shibata, Noriyuki Ouchi, Ryosuke Kikuchi, Ryotaro Takahashi, Kyosuke Takeshita, Yoshiyuki Kataoka, Koji Ohashi, Nobuo Ikeda, Shinji Kihara, Toyoaki Murohara

ATHEROSCLEROSIS Vol. 219 ( 2 ) page： 811 - 814 2011.12

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Objective: Obesity is closely associated with an increased risk for cardiovascular morbidity and mortality. Omentin is a fat-derived secreted factor that is downregulated in obesity. We investigated whether circulating omentin associates with the prevalence of coronary artery disease (CAD).
Methods: The consecutive 78 male subjects were enrolled from patients who underwent coronary angiography. Sixty one age-matched male subjects served as controls. Plasma omentin concentration was measured by enzyme-linked immunosorbent assay.
Results: Plasma levels of omentin correlated negatively with body mass index (BMI), systolic blood pressure, hemoglobin A1c and total cholesterol levels, and positively with HDL cholesterol and adiponectin levels. Circulating omentin was independently associated with hemoglobin A1c and HDL cholesterol in a multiple regression analysis. Plasma levels of omentin were markedly lower in CAD patients than in control subjects (CAD: 102.8 +/- 69.0 ng/ml, control: 454.7 +/- 128.6 ng/ml, P<0.001). Multiple logistic regression analysis with BMI, systolic blood pressure, glucose, hemoglobin A1c, HDL cholesterol, adiponectin and omentin revealed that plasma omentin levels were independently correlated with CAD.
Conclusion: These data indicate that low levels of omentin are closely linked with the presence of CAD and that omentin serves as a novel biomarker for CAD. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.atherosclerosis.2011.08.017

Association of a fat-derived plasma protein omentin with carotid artery intima-media thickness in apparently healthy men Reviewed

Rei Shibata, Ryotaro Takahashi, Yoshiyuki Kataoka, Koji Ohashi, Nobuo Ikeda, Shinji Kihara, Toyoaki Murohara, Noriyuki Ouchi

HYPERTENSION RESEARCH Vol. 34 ( 12 ) page： 1309 - 1312 2011.12

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Obesity is causally linked with the development of atherosclerosis. Omentin is an adipocytokine whose concentrations are reduced in obese individuals. Here we examined the relationship between plasma omentin levels and carotid intima-media thickness (IMT), a marker of early atherosclerosis, in apparently healthy Japanese men. Participants were 100 Japanese men who underwent a medical checkup. Maximal IMT (max-IMT) and mean-IMT in common carotid artery were measured by high-resolution carotid ultrasound system. Plasma omentin concentrations were determined by enzyme-linked immunosorbent assay. Circulating omentin levels correlated negatively with body mass index, waist circumference, fasting glucose, creatinine, max-IMT and mean-IMT, and positively with estimated glomerular filtration rates (eGFR). Single regression analysis demonstrated that max-IMT associated with age, eGFR and omentin levels, and that mean-IMT associated with age, fasting glucose, eGFR and omentin levels. Multiple regression analysis revealed that omentin levels, together with age, correlated with max-IMT and mean-IMT. Our data document that circulating omentin levels independently and negatively associate with carotid IMT in this population, suggesting that measurement of omentin may be useful for assessment of carotid IMT. Hypertension Research (2011) 34, 1309-1312; doi:10.1038/hr.2011.130; published online 4 August 2011

DOI： 10.1038/hr.2011.130

Cardiac myocyte follistatin-like 1 functions to attenuate hypertrophy following pressure overload Reviewed

Masayuki Shimano, Noriyuki Ouchi, Kazuto Nakamura, Bram van Wijk, Koji Ohashi, Yasuhide Asaumi, Akiko Higuchi, David R. Pimentel, Flora Sam, Toyoaki Murohara, Maurice J. B. van den Hoff, Kenneth Walsh

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Vol. 108 ( 43 ) page： E899 - E906 2011.10

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：NATL ACAD SCIENCES

Factors secreted by the heart, referred to as "cardiokines," have diverse actions in the maintenance of cardiac homeostasis and remodeling. Follistatin-like 1 (Fstl1) is a secreted glycoprotein expressed in the adult heart and is induced in response to injurious conditions that promote myocardial hypertrophy and heart failure. The aim of this study was to investigate the role of cardiac Fstl1 in the remodeling response to pressure overload. Cardiac myocyte-specific Fstl1-KO mice were constructed and subjected to pressure overload induced by transverse aortic constriction (TAC). Although Fstl1-KO mice displayed no detectable baseline phenotype, TAC led to enhanced cardiac hypertrophic growth and a pronounced loss in ventricular performance by 4 wk compared with control mice. Conversely, mice that acutely or chronically overexpressed Fstl1 were resistant to pressure overload-induced hypertrophy and cardiac failure. Fstl1-deficient mice displayed a reduction in TAC-induced AMP-activated protein kinase (AMPK) activation in heart, whereas Fstl1 overexpression led to increased myocardial AMPK activation under these conditions. In cultured neonatal cardiomyocytes, administration of Fstl1 promoted AMPK activation and antagonized phenylephrine-induced hypertrophy. Inhibition of AMPK attenuated the antihypertrophic effect of Fstl1 treatment. These results document that cardiac Fstl1 functions as an autocrine/paracrine regulatory factor that antagonizes myocyte hypertrophic growth and the loss of ventricular performance in response to pressure overload, possibly through a mechanism involving the activation of the AMPK signaling axis.

DOI： 10.1073/pnas.1108559108

Adipolin/C1qdc2/CTRP12 protein functions as an adipokine that improves glucose metabolism. Reviewed

Enomoto T, Ohashi K, Shibata R, Higuchi A, Maruyama S, Izumiya Y, Walsh K, Murohara T, Ouchi N.

The Journal of Biological Chemistry 2011.10

Adipolin/C1qdc2/CTRP12 Protein Functions as an Adipokine That Improves Glucose Metabolism Reviewed

Takashi Enomoto, Koji Ohashi, Rei Shibata, Akiko Higuchi, Sonomi Maruyama, Yasuhiro Izumiya, Kenneth Walsh, Toyoaki Murohara, Noriyuki Ouchi

JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 286 ( 40 ) page： 34552 - 34558 2011.10

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Obesity is a major risk factor for the development of insulin resistance and type 2 diabetes. Adipose tissue secretes various bioactive molecules, referred to as adipokines, whose dysregulation can mediate changes in glucose homeostasis and inflammatory responses. Here, we identify C1qdc2/CTRP12 as an insulin-sensitizing adipokine that is abundantly expressed by fat tissues and designate this adipokine as adipolin (adipose-derived insulin-sensitizing factor). Adipolin expression in adipose tissue and plasma was reduced in rodent models of obesity. Adipolin expression was also decreased in cultured 3T3-L1 adipocytes by treatment with inducers of endoplasmic reticulum stress and inflammation. Systemic administration of adipolin ameliorated glucose intolerance and insulin resistance in diet-induced obese mice. Adipolin administration also reduced macrophage accumulation and proinflammatory gene expression in the adipose tissue of obese mice. Conditioned medium from adipolin-expressing cells diminished the expression of proinflammatory cytokines in response to stimulation with LPS or TNF alpha in cultured macrophages. These data suggest that adipolin functions as an anti-inflammatory adipokine that exerts beneficial actions on glucose metabolism. Therefore, adipolin represents a new target molecule for the treatment of insulin resistance and diabetes.

DOI： 10.1074/jbc.M111.277319

Adiponectin Ameliorates Doxorubicin-induced Cardiotoxicity through Akt Protein-dependent Mechanism Reviewed

Sonomi Maruyama, Rei Shibata, Koji Ohashi, Taiki Ohashi, Hiroyuki Daida, Kenneth Walsh, Toyoaki Murohara, Noriyuki Ouchi

JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 286 ( 37 ) page： 32790 - 32800 2011.9

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Accumulating evidence shows that obesity is associated with doxorubicin cardiac toxicity in the heart, but the molecular mechanisms that contribute to this pathological response are not understood. Adiponectin is an adipose-derived, cardioprotective factor that is down-regulated in obesity. Here, we investigated the effect of adiponectin on doxorubicin (DOX)-induced cardiotoxicity and assessed the mechanisms of this effect. A single dose of DOX was intraperitoneally injected into the abdomen of adiponectin knock-out (APN-KO) and wild-type (WT) mice. APN-KO mice had increased mortality and exacerbated contractile dysfunction of left ventricle compared with WT mice. APN-KO mice also showed increased apoptotic activity and diminished Akt signaling in the failing myocardium. Systemic delivery of adenoviral vector expressing adiponectin improved left ventricle dysfunction and myocardial apoptosis following DOX injection in WT and APN-KO mice but not in Akt1 heterozygous KO mice. In cultured rat neonatal cardiomyocytes, adiponectin stimulated Akt phosphorylation and inhibited DOX-stimulated apoptosis. Treatment with sphingosine kinase-1 inhibitor or sphingosine 1-phosphate receptor antagonist diminished adiponectin-induced Akt phosphorylation and reversed the inhibitory effects of adiponectin on myocyte apoptosis. Pretreatment with anti-calreticulin antibody reduced the binding of adiponectin to cardiac myocytes and blocked the adiponectin-stimulated increase in Akt activation and survival in cardiomyocytes. Interference of the LRP1/calreticulin co-receptor system by siRNA or blocking antibodies diminished the stimulatory actions of adiponectin on Akt activation and myocyte survival. These data show that adiponectin protects against DOX-induced cardiotoxicity by its ability to promote Akt signaling.

DOI： 10.1074/jbc.M111.245985

Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling Reviewed

Eric E. Essick, Noriyuki Ouchi, Richard M. Wilson, Koji Ohashi, Joanna Ghobrial, Rei Shibata, David R. Pimentel, Flora Sam

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Vol. 301 ( 3 ) page： H984 - H993 2011.9

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：AMER PHYSIOLOGICAL SOC

Essick EE, Ouchi N, Wilson RM, Ohashi K, Ghobrial J, Shibata R, Pimentel DR, Sam F. Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling. Am J Physiol Heart Circ Physiol 301: H984-H993, 2011. First published June 10, 2011; doi:10.1152/ajpheart.00428.2011.-Reactive oxygen species (ROS) induce matrix metalloproteinase (MMP) activity that mediates hypertrophy and cardiac remodeling. Adiponectin (APN), an adipokine, modulates cardiac hypertrophy, but it is unknown if APN inhibits ROS-induced cardiomyocyte remodeling. We tested the hypothesis that APN ameliorates ROS-induced cardiomyocyte remodeling and investigated the mechanisms involved. Cultured adult rat ventricular myocytes (ARVM) were pretreated with recombinant APN (30 mu g/ml, 18 h) followed by exposure to physiologic concentrations of H2O2 (1-200 mu M). ARVM hypertrophy was measured by [H-3]leucine incorporation and atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) gene expression by RT-PCR. MMP activity was assessed by in-gel zymography. ROS was induced with angiotensin (ANG)-II (3.2 mg.kg(-1).day(-1) for 14 days) in wild-type (WT) and APN-deficient (APN-KO) mice. Myocardial MMPs, tissue inhibitors of MMPs (TIMPs), p-AMPK, and p-ERK protein expression were determined. APN significantly decreased H2O2-induced cardiomyocyte hypertrophy by decreasing total protein, protein synthesis, ANF, and BNP expression. H2O2-induced MMP-9 and MMP-2 activities were also significantly diminished by APN. APN significantly increased p-AMPK in both nonstimulated and H2O2-treated ARVM. H2O2-induced p-ERK activity and NF-kappa B activity were both abrogated by APN pretreatment. ANG II significantly decreased myocardial p-AMPK and increased p-ERK expression in vivo in APN-KO vs. WT mice. ANG II infusion enhanced cardiac fibrosis and MMP-2-to-TIMP-2 and MMP-9-to-TIMP-1 ratios in APN-KO vs. WT mice. Thus APN inhibits ROS-induced cardiomyocyte remodeling by activating AMPK and inhibiting ERK signaling and NF-kappa B activity. Its effects on ROS and ultimately on MMP expression define the protective role of APN against ROS-induced cardiac remodeling.

DOI： 10.1152/ajpheart.00428.2011

Adiponectin and hypertension. Reviewed

Ohashi K, Ouchi N, Matsuzawa Y.

American Journal of Hypertensions 2011.3

Association of Adiponectin with Carotid Arteriosclerosis in Predialysis Chronic Kidney Disease Reviewed

Mutsuharu Hayashi, Rei Shibata, Hiroshi Takahashi, Hideki Ishii, Toru Aoyama, Hirotake Kasuga, Shigeki Yamada, Koji Ohashi, Syoichi Maruyama, Seiichi Matsuo, Noriyuki Ouchi, Toyoaki Murohara, Takanobu Toriyama

AMERICAN JOURNAL OF NEPHROLOGY Vol. 34 ( 3 ) page： 249 - 255 2011

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：KARGER

Background/Aims: Adiponectin is an adipocyte-derived protein with antiatherogenic properties. Chronic kidney disease (CKD) is one of the risk factors for cardiovascular disease. We investigated the potential association between adiponectin and carotid arteriosclerosis in patients with predialysis CKD. Methods: We enrolled 95 CKD patients without dialysis and 81 non-CKD patients. Intima-media thickness (IMT) and plaque score (PS) in the common carotid artery were measured using an ultrasound system. Carotid arteriosclerosis was defined as IMT > 1.2 mm and/or PS > 5.0 mm. Results: The prevalence of CKD was independently associated with carotid arteriosclerosis after adjustment for other risk factors. Higher adiponectin levels were observed in CKD patients compared with non-CKD patients. Adiponectin levels were not independently correlated with the presence of carotid arteriosclerosis in all subjects. To evaluate the association between adiponectin and carotid arteriosclerosis among a CKD population, we divided the CKD patients into 2 groups according to a cutoff level of adiponectin determined by ROC analysis. The prevalence of carotid arteriosclerosis was significantly higher in the low-adiponectin group than in the high-adiponectin group among CKD patients. After adjusting for other risk factors, low levels of adiponectin were independently correlated with carotid arteriosclerosis in CKD patients. Conclusion: Our data document that adiponectin is associated with increased risk of carotid atherosclerosis in a predialysis CKD population. Copyright (C) 2011 S. Karger AG, Basel

DOI： 10.1159/000330178

Fenofibrate promotes ischemia-induced revascularization through the adiponectin-dependent pathway Reviewed

Ping Li, Rei Shibata, Sonomi Maruyama, Megumi Kondo, Koji Ohashi, Noriyuki Ouchi, Toyoaki Murohara

AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM Vol. 299 ( 4 ) page： E560 - E566 2010.10

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：AMER PHYSIOLOGICAL SOC

Li P, Shibata R, Maruyama S, Kondo M, Ohashi K, Ouchi N, Murohara T. Fenofibrate promotes ischemia-induced revascularization through the adiponectin-dependent pathway. Am J Physiol Endocrinol Metab 299: E560-E566, 2010. First published July 27, 2010; doi: 10.1152/ajpendo.00284.2010.-Recent clinical trials demonstrated that PPAR alpha agonist fenofibrate reduces cardiovascular events, including limb amputation in people with type 2 diabetes. Here, we investigated whether fenofibrate modulates the revascularization process in a mouse model of hindlimb ischemia. Treatment with fenofibrate led to acceleration of revascularization of ischemic hindlimb relative to the contralatereal limb in wild-type (WT) mice, as measured by laser Doppler blood flow and capillary density analyses. Treatment of WT mice with fenofibrate increased the serum levels of adiponectin, which has protective actions on the vasculature. Of importance, fenofibrate had no effects on the revascularization in ischemic limbs of adiponectin-deficient (APN-KO) mice. Fenofibrate stimulated the phosphorylation of AMPK and eNOS in the ischemic muscles in WT mice but not in APN-KO mice. AMPK inhibitor compound C suppressed fenofibrate-induced increase in limb perfusion and AMPK phosphorylation in ischemic muscle in WT mice without affecting adiponectin levels. NOS inhibitor L-NAME also blocked the increased blood flow of ischemic limbs in fenofibrate-treated WT mice. Our observations suggest that fenofibrate could promote revascularization in response to ischemia through adiponectin-dependent AMPK signaling.

DOI： 10.1152/ajpendo.00284.2010

Adiponectin deficiency exacerbates cardiac dysfunction following pressure overload through disruption of an AMPK-dependent angiogenic response Reviewed

Masayuki Shimano, Noriyuki Ouchi, Rei Shibata, Koji Ohashi, David R. Pimentel, Toyoaki Murohara, Kenneth Walsh

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY Vol. 49 ( 2 ) page： 210 - 220 2010.8

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD

Although increasing evidence indicates that an adipokine adiponectin exerts protective actions on heart, its effects on coronary angiogenesis following pressure overload have not been examined previously. Because disruption of angiogenesis during heart growth leads to contractile dysfunction and heart failure, we hypothesized that adiponectin modulates cardiac remodeling in response to pressure overload through its ability to regulate adaptive angiogenesis. Adiponectin-knockout (APN-KO) and wild-type (WT) mice were subjected to pressure overload caused by transverse aortic constriction (TAC). APN-KO mice exhibited greater cardiac hypertrophy, pulmonary congestion, left ventricular (LV) interstitial fibrosis and LV systolic dysfunction after TAC surgery compared with WT mice. APN-KO mice also displayed reduced capillary density in the myocardium after TAC, which was accompanied by a significant decrease in expression of vascular endothelial growth factor (VEGF) and phosphorylation of AMP-activated protein kinase (AMPK). Inhibition of AMPK in WT mice resulted in aggravated LV systolic function, attenuated myocardial capillary density and decreased VEGF expression in response to TAC. The adverse effects of AMPK inhibition on cardiac function and angiogenic response following TAC were diminished in APN-KO mice relative to WT mice. Moreover, adenovirus-mediated VEGF delivery reversed the TAC-induced deficiencies in cardiac microvessel formation and ventricular function observed in the APN-KO mice. In cultured cardiac myocytes, adiponectin treatment stimulated VEGF production, which was inhibited by inactivation of AMPK signaling pathway. Collectively, these data show that adiponectin deficiency can accelerate the transition from cardiac hypertrophy to heart failure during pressure overload through disruption of AMPK-dependent angiogenic regulatory axis. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.yjmcc.2010.02.021

Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity. Reviewed

Ouchi N, Higuchi A, Ohashi K, Oshima Y, Gokce N, Shibata R, Akasaki Y, Shimono A, Walsh K.

Science 2010.7

LKB1 deficiency in Tie2-Cre-expressing cells impairs ischemia-induced angiogenesis. Reviewed

Ohashi K, Ouchi N, Higuchi A, Shaw RJ, Walsh K.

The Journal of Biological Chemistry 2010.7

Modulation of Angiotensin II-Mediated Cardiac Remodeling by the MEF2A Target Gene Xirp2 Reviewed

Sarah A. McCalmon, Danielle M. Desjardins, Saad Ahmad, Katharine S. Davidoff, Christine M. Snyder, Kaori Sato, Koji Ohashi, Ondra M. Kielbasa, Matthen Mathew, Elizabeth P. Ewen, Kenneth Walsh, Haralambos Gavras, Francisco J. Naya

CIRCULATION RESEARCH Vol. 106 ( 5 ) page： 952 - 60 2010.3

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Rationale: The vasoactive peptide angiotensin II (Ang II) is a potent cardiotoxic hormone whose actions have been well studied, yet questions remain pertaining to the downstream factors that mediate its effects in cardiomyocytes.
Objective: The in vivo role of the myocyte enhancer factor (MEF)2A target gene Xirp2 in Ang II-mediated cardiac remodeling was investigated.
Methods and Results: Here we demonstrate that the MEF2A target gene Xirp2 (also known as cardiomyopathy associated gene 3 [CMYA3]) is an important effector of the Ang II signaling pathway in the heart. Xirp2 belongs to the evolutionarily conserved, muscle-specific, actin-binding Xin gene family and is significantly induced in the heart in response to systemic administration of Ang II. Initially, we characterized the Xirp2 promoter and demonstrate that Ang II activates Xirp2 expression by stimulating MEF2A transcriptional activity. To further characterize the role of Xirp2 downstream of Ang II signaling we generated mice harboring a hypomorphic allele of the Xirp2 gene that resulted in a marked reduction in its expression in the heart. In the absence of Ang II, adult Xirp2 hypomorphic mice displayed cardiac hypertrophy and increased beta myosin heavy chain expression. Strikingly, Xirp2 hypomorphic mice chronically infused with Ang II exhibited altered pathological cardiac remodeling including an attenuated hypertrophic response, as well as diminished fibrosis and apoptosis.
Conclusions: These findings reveal a novel MEF2A-Xirp2 pathway that functions downstream of Ang II signaling to modulate its pathological effects in the heart. (Circ Res. 2010; 106: 952-960.)

DOI： 10.1161/CIRCRESAHA.109.209007

DIP2A Functions as a FSTL1 Receptor Reviewed

Noriyuki Ouchi, Yasuhide Asaumi, Koji Ohashi, Akiko Higuchi, Saki Sono-Romanelli, Yuichi Oshima, Kenneth Walsh

JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 285 ( 10 ) page： 7127 - 34 2010.3

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

FSTL1 is an extracellular glycoprotein whose functional significance in physiological and pathological processes is incompletely understood. Recently, we have shown that FSTL1 acts as a muscle-derived secreted factor that is up-regulated by Akt activation and ischemic stress and that FSTL1 exerts favorable actions on the heart and vasculature. Here, we sought to identify the receptor that mediates the cellular actions of FSTL1. We identified DIP2A as a novel FSTL1-binding partner from the membrane fraction of endothelial cells. Co-immunoprecipitation assays revealed a direct physical interaction between FSTL1 and DIP2A. DIP2A was present on the cell surface of endothelial cells, and knockdown of DIP2A by small interfering RNA reduced the binding of FSTL1 to cells. In cultured endothelial cells, knockdown of DIP2A by small interfering RNA diminished FSTL1-stimulated survival, migration, and differentiation into network structures and inhibited FSTL1-induced Akt phosphorylation. In cultured cardiac myocytes, ablation of DIP2A reduced the protective actions of FSTL1 on hypoxia/reoxygenation-induced apoptosis and suppressed FSTL1-induced Akt phosphorylation. These data indicate that DIP2A functions as a novel receptor that mediates the cardiovascular protective effects of FSTL1.

DOI： 10.1074/jbc.M109.069468

Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. Reviewed

Ohashi K, Parker JL, Ouchi N, Higuchi A, Vita JA, Gokce N, Pedersen AA, Kalthoff C, Tullin S, Sams A, Summer R, Walsh K.

The Journal of Biological Chemistry 2010.2

Thiazolidinediones reduce pathological neovascularization in ischemic retina via an adiponectin-dependent mechanism. Reviewed

Higuchi A, Ohashi K, Shibata R, Sono-Romanelli S, Walsh K, Ouchi N.

Arteriosclerosis, Thrombosis, and Vascular Biology 2010.1

Adiponectin Deficiency, Diastolic Dysfunction, and Diastolic Heart Failure Reviewed

Flora Sam, Toni-Ann S. Duhaney, Kaori Sato, Richard M. Wilson, Koji Ohashi, Saki Sono-Romanelli, Akiko Higuchi, Deepa S. De Silva, Fuzhong Qin, Kenneth Walsh, Noriyuki Ouchi

ENDOCRINOLOGY Vol. 151 ( 1 ) page： 322 - 31 2010.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ENDOCRINE SOC

Aldosterone infusion results in left ventricular hypertrophy (LVH) and hypertension and may involve profibrotic and proinflammatory mechanisms. In turn, hypertension is the major cause of diastolic heart failure (HF). Adiponectin, an adipose-derived plasma protein, exerts antiinflammatory and anti-hypertrophic effects and is implicated in the development of hypertension and systolic HF. We thus tested the hypothesis that hypoadiponectinemia in aldosterone-induced hypertension exacerbated cardiac remodeling and diastolic HF. Wild-type (WT) or adiponectin-deficient (APNKO) mice underwent saline or aldosterone infusion and uninephrectomy and were fed 1% salt water for 4 wk. Blood pressure was increased in aldosterone-infused WT (132 +/- 2 vs. 109 +/- 3 mm Hg; P < 0.01) and further augmented in APNKO mice (140 +/- 3 mm Hg; P < 0.05 vs. aldosterone-infused WT). LVH was increased in aldosterone-infused WT vs. WT mice (LV/body weight ratio, 4.8 +/- 0.2 vs. 4.1 +/- 0.2 mg/g) and further increased in aldosterone-infused APNKO mice (LV/body weight ratio, 6.0 +/- 0.4 mg/g). Left ventricular ejection fraction was not decreased in either aldosterone-infused WT or APNKO hearts. Pulmonary congestion however was worse in APNKO mice (P < 0.01). The ratio of early ventricular filling over late ventricular filling (E/A) and the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity (E/e'), measures of diastolic function, were increased in aldosterone-infused WT hearts and further increased in APNKO hearts (P < 0.05 for both). Renal function and cardiac fibrosis were no different between both aldosterone-infused groups. Aldosterone increased matrix metalloproteinase-2 expression in WT hearts (P < 0.05 vs. WT and P < 0.01 vs. APNKO). Myocardial atrial natriuretic peptide, interferon-gamma, and TNF-alpha expression were increased in aldosterone-infused WT hearts. Expression of these proteins was further increased in aldosterone-infused APNKO hearts. Therefore, hypoadiponectinemia in hypertension-induced diastolic HF exacerbates LVH, diastolic dysfunction, and diastolic HF. Whether or not adiponectin replacement prevents the progression to diastolic HF will warrant further study. (Endocrinology 151: 322-331, 2010)

DOI： 10.1210/en.2009-0806

Adiponectin suppresses pathological microvessel formation in retina through modulation of tumor necrosis factor-alpha expression. Reviewed

Higuchi A, Ohashi K, Kihara S, Walsh K, Ouchi N

Circulation Research 2009.5

Adiponectin promotes revascularization of ischemic muscle through a cyclooxygenase 2-dependent mechanism. Reviewed

Ohashi K, Ouchi N, Sato K, Higuchi A, Ishikawa TO, Herschman HR, Kihara S, Walsh K.

Molecular and Cellular Biology 2009.4

Follistatin-like 1, a Secreted Muscle Protein, Promotes Endothelial Cell Function and Revascularization in Ischemic Tissue through a Nitric-oxide Synthase-dependent Mechanism Reviewed

Noriyuki Ouchi, Yuichi Oshima, Koji Ohashi, Akiko Higuchi, Chiaki Ikegami, Yasuhiro Izumiya, Kenneth Walsh

JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 283 ( 47 ) page： 32802 - 32811 2008.11

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Myogenic Akt signaling coordinates blood vessel recruitment with normal tissue growth. Here, we investigated the role of Follistatin-like 1 (Fstl1) in the regulation of endothelial cell function and blood vessel growth in muscle. Transgenic Akt1 overexpression in skeletal muscle led to myofiber growth that was coupled to an increase in muscle capillary density. Myogenic Akt signaling or ischemic hind limb surgery led to the induction of Fstl1 in muscle and increased circulating levels of Fstl1. Intramuscular administration of an adenoviral vector expressing Fstl1 (Ad-Fstl1) accelerated flow recovery and increased capillary density in the ischemic hind limbs of wild-type mice, and this was associated with an increase in endothelial nitric oxide synthase (eNOS) phosphorylation at residue Ser-1179. In cultured endothelial cells, Ad-Fstl1 stimulated migration and differentiation into network structures and inhibited apoptosis under conditions of serum deprivation. These cell responses were associated with the activating phosphorylation of Akt and eNOS. Conversely, transduction with dominant-negative Akt or LY294002 blocked Fstl1-stimulated eNOS phosphorylation and inhibited Fstl1-stimulated cellular responses. Treatment with the eNOS inhibitor N-G-nitro-L-arginine methyl ester also reduced endothelial cell migration and differentiation induced by Ad-Fstl1. The stimulatory effect of Ad-Fstl1 on ischemic limb reperfusion was abolished in mice lacking eNOS. These data indicate that Fstl1 is a secreted muscle protein or myokine that can function to promote endothelial cell function and stimulates revascularization in response to ischemic insult through its ability to activate Akt-eNOS signaling.

DOI： 10.1074/jbc.M803440200

Adiponectin protects against angiotensin II-induced cardiac fibrosis through activation of PPAR-alpha Reviewed

Koichi Fujita, Norikazu Maeda, Mina Sonoda, Koji Ohashi, Toshiyuki Hibuse, Hitoshi Nishizawa, Makoto Nishida, Aki Hiuge, Akifumi Kurata, Shinji Kihara, Iichiro Shimomura, Tohru Funahashi

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Vol. 28 ( 5 ) page： 863 - 870 2008.5

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Objectives-Adiponectin is recognized as an antidiabetic, antiatherosclerotic, and anti-inflammatory protein derived from adipocytes. However, the role of adiponectin in cardiac fibrosis remains uncertain. We herein explore the effects of adiponectin on cardiac fibrosis induced by angiotensin II (Ang II).
Methods and Results-Wild-type (WT), adiponectin knockout (Adipo-KO), and PPAR-alpha knockout (PPAR-alpha-KO) mice were infused with Ang II at 1.2 mg/kg/d. Severe cardiac fibrosis and left ventricular dysfunction were observed in Ang II-infused Adipo-KO mice compared to WT mice. Adenovirus-mediated adiponectin treatment improved the above phenotypes and the dysregulation of reactive oxygen species (ROS)-related mRNAs in Adipo-KO mice, whereas such amelioration was not observed in PPAR-alpha-KO mice despite adiponectin accumulation in heart tissue. In cultured cardiac fibroblasts, adiponectin improved the reduction of AMP-activated protein kinase (AMPK) activity and elevation of extracellular signal-regulated kinase 1/2 (ERK1/2) activity induced by Ang II. Adiponectin significantly enhanced PPAR-alpha activity, whereas the adiponectin-dependent PPAR-alpha activation was diminished by Compound C, an inhibitor of AMPK.
Conclusion-The present study suggests that adiponectin protects against Ang II-induced cardiac fibrosis possibly through AMPK-dependent PPAR-alpha activation.

DOI： 10.1161/ATVBAHA.107.156687

Cyclooxygenase-2 induction by adiponectin is regulated by a sphingosine kinase-1 dependent mechanism in cardiac myocytes. Reviewed

Ikeda Y, Ohashi K, Shibata R, Pimentel DR, Kihara S, Ouchi N, Walsh K.

FEBS Letters 2008.4

Exacerbation of albuminuria and renal fibrosis in subtotal renal ablation model of adiponectin-knockout mice. Reviewed

Ohashi K, Iwatani H, Kihara S, Nakagawa Y, Komura N, Fujita K, Maeda N, Nishida M, Katsube F, Shimomura I, Ito T, Funahashi T.

Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 27 ( 9 ) page： 1910-1917 2007.7

Blockade of angiotensin II type-1 receptor reduces oxidative stress in adipose tissue and ameliorates adipocytokine dysregulation Reviewed

A. Kurata, H. Nishizawa, S. Kihara, N. Maeda, M. Sonoda, T. Okada, K. Ohashi, T. Hibuse, K. Fujita, A. Yasui, A. Hiuge, M. Kumada, H. Kuriyama, I. Shimomura, T. Funahashi

Kidney International Vol. 70 ( 10 ) page： 1717 - 1724 2006.11

Language：English Publishing type：Research paper (scientific journal)

Dysregulated production of adipocytokines may be involved in the development of atherosclerotic cardiovascular disease in metabolic syndrome and chronic kidney disease (CKD) associated with metabolic syndrome. The aim of this study was to determine the effects of treatment with angiotensin II (Ang II) type-1 receptor blocker (ARB) on the regulation of adipocytokines. Olmesartan, an ARB, significantly blunted the age- and body weight-associated falls in plasma adiponectin both in genetically and diet-induced obese mice, without affecting body weight, but had no effect on plasma adiponectin levels in lean mice. Olmesartan also ameliorated dysregulation of adipocytokines in obesity, such as tumor necrosis factor-α, plasminogen activator inhibitor-1, monocyte chemotactic protein-1, and serum amyloid A3. Olmesartan significantly reduced reactive oxygen species originating from accumulated fat and attenuated the expression of nicotinamide adenine dinucleotide phospho hydrogenase oxidase subunits in adipose tissue. In cultured adipocytes, olmesartan acted as an antioxidant and improved adipocytokine dysregulation. Our results indicate that blockade of Ang II receptor ameliorates adipocytokine dysregulation and that such action is mediated, at least in part, by targeting oxidative stress in obese adipose tissue. Ang II signaling and subsequent oxidative stress in adipose tissue may be potential targets for the prevention of atherosclerotic cardiovascular disease in metabolic syndrome and also in metabolic syndrome-based CKD. © 2006 International Society of Nephrology.

DOI： 10.1038/sj.ki.5001810

Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2 dependent mechanisms Reviewed

R Shibata, K Sato, DR Pimentel, Y Takemura, S Kihara, K Ohashi, T Funahashi, N Ouchi, K Walsh

NATURE MEDICINE Vol. 11 ( 10 ) page： 1096 - 1103 2005.10

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Obesity-related disorders are associated with the development of ischemic heart disease. Adiponectin is a circulating adipose-derived cytokine that is downregulated in obese individuals and after myocardial infarction. Here, we examine the role of adiponectin in myocardial remodeling in response to acute injury. Ischemia-reperfusion in adiponectin-deficient (APN-KO) mice resulted in increased myocardial infarct size, myocardial apoptosis and tumor necrosis factor (TNF)-alpha expression compared with wild-type mice. Administration of adiponectin diminished infarct size, apoptosis and TNF-alpha production in both APN-KO and wildtype mice. In cultured cardiac cells, adiponectin inhibited apoptosis and TNF-alpha production. Dominant negative AMP-activated protein kinase ( AMPK) reversed the inhibitory effects of adiponectin on apoptosis but had no effect on the suppressive effect of adiponectin on TNF-alpha production. Adiponectin induced cyclooxygenase (COX)-2-dependent synthesis of prostaglandin E-2 in cardiac cells, and COX-2 inhibition reversed the inhibitory effects of adiponectin on TNF-alpha production and infarct size. These data suggest that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX-2-dependent mechanisms.

DOI： 10.1038/nm1295

Association of hypoadiponectinemia with smoking habit in men Reviewed

Y Iwashima, T Katsuya, K Ishikawa, Kida, I, M Ohishi, T Horio, N Ouchi, K Ohashi, S Kihara, T Funahashi, H Rakugi, T Ogihara

HYPERTENSION Vol. 45 ( 6 ) page： 1094 - 1100 2005.6

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Adiponectin is emerging as an important molecule in obesity, the metabolic syndrome, and cardiovascular disease. On the other hand, smoking habit is well known to be related to cardiovascular disease and hypertension. To examine the association between adiponectin concentration and smoking habit, we performed an epidemiological survey and an acute exposure test in humans and an experiment in adipocytes to elucidate the mechanism underlying the association between adiponectin and smoking. In the epidemiological study, we enrolled a total of 331 male subjects to examine chronic smoking exposure. Plasma adiponectin was significantly lower ( P = 0.01) in current smokers ( 5.3 +/- 0.3 mu g/mL) than in never-smokers (6.5 +/- 0.4 mu g/mL). A significant association between smoking and low adiponectin level was also confirmed in multiple regression analysis including age, body mass index, hypertension, diabetes, hyperlipidemia, and creatinine clearance ( never- smokers 6.5 +/- 0.4 mu g/mL; past smokers 5.6 +/- 0.3 mu g/mL; current smokers 5.2 +/- 0.4 mu g/mL; F = 4.52; P = 0.01). To examine the acute effect of smoking on adiponectin concentration for 12 hours, we measured plasma adiponectin level in 5 male never- smokers before smoking and 3, 6, and 12 hours after smoking, with the result that adiponectin showed a significant decrease after smoking ( 12 hours; - 14.5 +/- 0.6%; P < 0.01). In cultured mouse 3T3-L1 adipocytes, H2O2 and nicotine reduced the mRNA expression and secretion of adiponectin in a dose-dependent manner. Smoking habit is associated with adiponectin concentration in men, and its suppressive effect is mediated in part through direct inhibition of smoking on adiponectin expression in adipocytes.

DOI： 10.1161/01.HYP.0000169444.05588.4c

Adiponectin replenishment ameliorates obesity-related hypertension. Reviewed

Ohashi K, Kihara S, Ouchi N, Kumada M, Fujita K, Hiuge A, Hibuse T, Ryo M, Nishizawa H, Maeda N, Maeda K, Shibata R, Walsh K, Funahashi T, Shimomura I.

Hypertension Vol. 47 ( 6 ) page： 1108-1116 2005.5

低アディポネクチン血症と高血圧との関係

大橋浩二, 木原進士, 岩嶋義雄, 船橋徹, 荻原俊男, 下村伊一郎, 松澤佑次

日本内科学会雑誌 Vol. 94 ( Suppl. ) page： 235 - 235 2005.2

Adiponectin-mediated modulation of hypertrophic signals in the heart Reviewed

R Shibata, N Ouchi, M Ito, S Kihara, Shiojima, I, DR Pimentel, M Kumada, K Sato, S Schiekofer, K Ohashi, T Funahashi, WS Colucci, K Walsh

NATURE MEDICINE Vol. 10 ( 12 ) page： 1384 - 1389 2004.12

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Patients with diabetes and other obesity-linked conditions have increased susceptibility to cardiovascular disorders(1). The adipocytokine adiponectin is decreased in patients with obesity-linked diseases(2). Here, we found that pressure overload in adiponectin-deficient mice resulted in enhanced concentric cardiac hypertrophy and increased mortality that was associated with increased extracellular signal-regulated kinase (ERK) and diminished AMP-activated protein kinase (AMPK) signaling in the myocardium. Adenovirus-mediated supplemention of adiponectin attenuated cardiac hypertrophy in response to pressure overload in adiponectin-deficient, wild-type and diabetic db/db mice. In cultures of cardiac myocytes, adiponectin activated AMPK and inhibited agonist-stimulated hypertrophy and ERK activation. Transduction with a dominant-negative form of AMPK reversed these effects, suggesting that adiponectin inhibits hypertrophic signaling in the myocardium through activation of AMPK signaling. Adiponectin may have utility for the treatment of hypertrophic cardiomyopathy associated with diabetes and other obesity-related diseases.

DOI： 10.1038/nm1137

メタボリックシンドロームにおける高血圧とアディポネクチンとの関連について

大橋浩二, 岩嶋義雄, 木原進士, 船橋徹, 勝谷友宏, 荻原俊男, 下村伊一郎

肥満研究 Vol. 10 ( Suppl. ) page： 122 - 122 2004.9

Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages Reviewed

M Kumada, S Kihara, N Ouchi, H Kobayashi, Y Okamoto, K Ohashi, K Maeda, H Nagaretani, K Kishida, N Maeda, A Nagasawa, T Funahashi, Y Matsuzawa

CIRCULATION Vol. 109 ( 17 ) page： 2046 - 2049 2004.5

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Background - Vascular inflammation and subsequent matrix degradation play an important role in the development of atherosclerosis. We previously reported that adiponectin, an adipose-specific plasma protein, accumulated to the injured artery and attenuated vascular inflammatory response. Clinically, high plasma adiponectin level was associated with low cardiovascular event rate in patients with chronic renal failure. The present study was designed to elucidate the effects of adiponectin on matrix metalloproteinases ( MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in human monocyte-derived macrophages.
Methods and Results - Human monocyte-derived macrophages were incubated with the physiological concentrations of human recombinant adiponectin for the time indicated. Adiponectin treatment dose-dependently increased TIMP-1 mRNA levels without affecting MMP-9 mRNA levels. Adiponectin also augmented TIMP-1 secretion into the media, whereas MMP-9 secretion and activity were unchanged. Time course experiments indicated that TIMP-1 mRNA levels started to increase at 24 hours of adiponectin treatment and were significantly elevated at 48 hours. Adiponectin significantly increased interleukin-10 (IL-10) mRNA expression at the transcriptional level within 6 hours and significantly increased IL-10 protein secretion within 24 hours. Cotreatment of adiponectin with anti-IL-10 monoclonal antibody completely abolished adiponectin-induced TIMP-1 mRNA expression.
Conclusions - Adiponectin selectively increased TIMP-1 expression in human monocyte-derived macrophages through IL-10 induction. This study identified, for the first time, the adiponectin/IL-10 interaction against vascular inflammation.

DOI： 10.1161/01.CIR.0000127953.98131.ED

Adiponectin I164T mutation is associated with the metabolic syndrome and coronary artery disease. Reviewed

Ohashi K, Ouchi N, Kihara S, Funahashi T, Nakamura T, Sumitsuji S, Kawamoto T, Matsumoto S, Nagaretani H, Kumada M, Okamoto Y, Nishizawa H, Kishida K, Maeda N, Hiraoka H, Iwashima Y, Ishikawa K, Ohishi M, Katsuya T, Rakugi H, Ogihara T, Matsuzawa Y.

Journal of American College of Cardiology Vol. 43 ( 7 ) page： 1195-1200 2004.4

Association of hypoadiponectinemia with impaired vasoreactivity Reviewed

N Ouchi, M Ohishi, S Kihara, T Funahashi, T Nakamura, H Nagaretani, M Kumada, K Ohashi, Y Okamoto, H Nishizawa, K Kishida, N Maeda, A Nagasawa, H Kobayashi, H Hiraoka, N Komai, M Kaibe, H Rakugi, T Ogihara, Y Matsuzawa

HYPERTENSION Vol. 42 ( 3 ) page： 231 - 234 2003.9

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Endothelial dysfunction is a crucial feature in the evolution of atherosclerosis. Adiponectin is an adipocyte-specific plasma protein with antiatherogenic and antidiabetic properties. In the present study, we investigated the relation between adiponectin and endothelium-dependent vasodilation. We analyzed endothelial function in 202 hypertensive patients, including those who were not taking any medication. Forearm blood flow was measured by strain-gauge plethysmography. Plasma adiponectin level was highly correlated with the vasodilator response to reactive hyperemia in the total ( r = 0.257, P < 0.001) and no-medication ( r = 0.296, P = 0.026) groups but not with nitroglycerin-induced hyperemia, indicating that adiponectin affected endothelium-dependent vasodilation. Multiple regression analysis of data from all hypertensive patients revealed that plasma adiponectin level was independently correlated with the vasodilator response to reactive hyperemia. Vascular reactivity was also analyzed in aortic rings from adiponectin-knockout ( KO) and wild-type (WT) mice. Adiponectin-KO mice showed obesity, hyperglycemia, and hypertension compared with WT mice after 4 weeks on an atherogenic diet. Endothelium-dependent vasodilation in response to acetylcholine was significantly reduced in adiponectin-KO mice compared with WT mice, although no significant difference was observed in endothelium-independent vasodilation in response to sodium nitroprusside. Our observations suggest that hypoadiponectinemia is associated with impaired endothelium-dependent vasorelaxation and that the measurement of plasma adiponectin level might be helpful as a marker of endothelial dysfunction.

DOI： 10.1161/01.HYP.0000083488.67550.B8

Disturbed secretion of mutant adiponectin associated with the metabolic syndrome Reviewed

K Kishida, H Nagaretani, H Kondo, H Kobayashi, S Tanaka, N Maeda, A Nagasawa, T Hibuse, K Ohashi, M Kumada, H Nishizawa, Y Okamoto, N Ouchi, K Maeda, S Kihara, T Funahashi, Y Matsuzawa

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Vol. 306 ( 1 ) page： 286 - 292 2003.6

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Adiponectin, an adipocyte-derived protein, consists of collagen-like fibrous and complement C1q-like globular domains, and circulates in human plasma in a multimeric form. The protein exhibits anti-diabetic and anti-atherogenic activities. However, adiponectin plasma concentrations are low in obese subjects, and hypoadiponectinemia is associated with the metabolic syndrome, which is a cluster of insulin resistance, type 2 diabetes mellitus, hypertension, and dyslipidemia. We have recently reported a missense mutation in the adiponectin gene, in which isoleucine at position 164 in the globular domain is substituted with threonine (I164T). Subjects with this mutation showed markedly low level of plasma adiponectin and clinical features of the metabolic syndrome. Here, we examined the molecular characteristics of the mutant protein associated with a genetic cause of hypoadiponectinemia. The current study revealed (1) the mutant protein showed an oligomerization state similar to the wild-type as determined by gel filtration chromatography and, (2) the mutant protein exhibited normal insulin-sensitizing activity, but (3) pulse-chase study showed abnormal secretion of the mutant protein from adipose tissues. Our results suggest that I164T mutation is associated with hypoadiponectinemia through disturbed secretion into plasma, which may contribute to the development of the metabolic syndrome. (C) 2003 Elsevier Science (USA). All rights reserved.

DOI： 10.1016/S0006-291X(03)00940-9

Measurement of fasting serum apoB-48 levels in normolipidemic and hyperlipidemic subjects by ELISA Reviewed

N Sakai, Y Uchida, K Ohashi, T Hibuse, Y Saika, Y Tomari, S Kihara, H Hiraoka, T Nakamura, S Ito, S Yamashita, Y Matsuzawa

JOURNAL OF LIPID RESEARCH Vol. 44 ( 6 ) page： 1256 - 1262 2003.6

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPID RESEARCH INC

The present study was designed to evaluate the metabolism of chylomicron and chylomicron remnants by measuring serum apolipoprotein B-48 (apoB-48) levels in 335 normolipidemic and 253 hyperlipidemic subjects using a novel ELISA system. The distribution of fasting serum apoB-48 levels in normolipidemic subjects varied widely, ranging from <1 to >24 mug/ml (mean, 5.2 +/- 3.8 mug/ml; median, 3.9 mug/ml). Serum apoB-48 levels correlated with serum triglyceride (TG) concentrations (r = 0.45, P < 0.001), but not with total cholesterol levels. Serum apoB-48 levels were 7 to 18 times higher in patients with Type 1, Type V, and Type III hyperlipidemia, and only slightly higher in patients with Type IIa, Type IIb, and Type IV hyperlipidemia, compared with normolipidemic subjects. The calculated apoB-48/TG ratio was elevated only in patients with dysbetalipoproteinemia (apoE2/2 phenotype). In normolipidemic subjects, oral fat loading resulted in about 2-fold increase in serum apoB-48 levels, with a peak level recorded at 3-4 h postloading, and then returned to the baseline level within 6 h. On the other hand, in patients with dysbetalipoproteinemia, serum apoB-48 levels did not change considerably.jlr Our results indicate that serum apoB-48 is a very useful parameter for evaluating lipoprotein metabolism in exogenous pathways.

DOI： 10.1194/jlr.M300090-JLR200

Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue Reviewed

N Ouchi, S Kihara, T Funahashi, T Nakamura, M Nishida, M Kumada, Y Okamoto, K Ohashi, H Nagaretani, K Kishida, H Nishizawa, N Maeda, H Kobayashi, H Hiraoka, Y Matsuzawa

CIRCULATION Vol. 107 ( 5 ) page： 671 - 674 2003.2

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Background-High-sensitive C-reactive protein (hs-CRP) is a well-known risk factor for coronary artery disease (CAD). Recently, we have demonstrated that adiponectin served as an antiatherogenic plasma protein which was secreted specifically from adipocytes. The present study investigated the association between adiponectin and CRP in the blood stream and adipose tissue.
Methods and Results-We studied a total of 101 male patients, 71 of whom had angiographically documented coronary atherosclerosis. As a control group, 30 patients with normal coronary angiogram were included. The plasma hs-CRP levels were negatively correlated with the plasma adiponectin levels (r= -0.29, P<0.01). The plasma adiponectin concentrations were significantly lower and the hs-CRP levels were significantly higher in the CAD patients compared with control subjects. The mRNA levels of CRP and adiponectin were analyzed by quantitative real-time polymerase chain reaction method. We found that the CRP mRNA was expressed in human adipose tissue. A significant inverse correlation was observed between the CRP and adiponectin mRNA levels in human adipose tissue (r=-0.89, P<0.01). In addition, the CRP mRNA level of white adipose tissue in adiponectin deficient mice was higher than that of wild-type mice.
Conclusions-The reciprocal association of adiponectin and CRP levels in both human plasma and adipose tissue might participate in the development of atherosclerosis.

DOI： 10.1161/01.CIR.0000055188.83694.B3

Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice Reviewed

Y Okamoto, S Kihara, N Ouchi, M Nishida, Y Arita, M Kumada, K Ohashi, N Sakai, Shimomura, I, H Kobayashi, N Terasaka, T Inaba, T Funahashi, Y Matsuzawa

CIRCULATION Vol. 106 ( 22 ) page： 2767 - 2770 2002.11

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Background-Dysregulation of adipocyte-derived bioactive molecules plays an important role in the development of atherosclerosis., We previously reported that adiponectin, an adipocyte-specific plasma protein, accumulated in the injured artery from the plasma and suppressed endothelial inflammatory response and vascular smooth muscle cell proliferation, as well as macrophage-to-foam cell transformation in vitro. The current study investigated whether the increased plasma adiponectin could actually reduce atherosclerosis in vivo.
Methods and Results-Apolipoprotein E-deficient mice were treated with recombinant adenovirus expressing human adiponectin (Ad-APN) or beta-galactosidase (Ad-betagal). The plasma adiponectin levels in Ad-APN-treated mice increased 48 times as much as those in Ad-betagal treated mice. On the 14th day after injection, the lesion formation in aortic sinus was inhibited in Ad-APN-treated mice by 30% compared with Ad-betagal-treated mice (P<0.05). In the lesions. of Ad-APN-treated mice, the lipid droplets became smaller compared with Ad-betagal-treated mice (P<0.01). Immunohistochemical analyses demonstrated that the adenovirus-mediated adiponectin migrate to foam cells in the fatty streak lesions. The real-time quantitative polymerase chain reaction revealed that Ad-APN treatment significantly suppressed the mRNA levels of vascular cell adhesion molecule-1 by 29% and class A scavenger receptor by 34%, and tended to reduce levels of tumor necrosis factor-alpha without affecting those of CD36 in the aortic tissue.
Conclusions-These findings documented for the first time that elevated plasma adiponectin suppresses the development of atherosclerosis in vivo.

DOI： 10.1161/01.CIR.0000042707.50032.19

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