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

Web of Science

PubMed

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

Web of Science

PubMed

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

Web of Science

PubMed

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

Web of Science

PubMed

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

Web of Science

PubMed

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

Web of Science

PubMed

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

Web of Science

PubMed

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

Web of Science

PubMed

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

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

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Papers - OHASHI, Koji