Faculty Profiles - TAKEFUJI Mikito

Papers - TAKEFUJI Mikito

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Urocortin2 measurement for heart failure assessment. Open Access

Inukai K, Miyashita K, Kotani K, Morimoto R, Kondo T, Hiraiwa H, Kazama S, Yoshida T, Yoshida S, Hattori T, Fukamachi K, Fukui N, Kato K, Yura Y, Ohashi K, Ouchi N, Murohara T, Okumura T, Takefuji M

Scientific reports Vol. 15 ( 1 ) page： 14381 2025.4

Language：English Publisher：Scientific Reports

Despite the efficacy of many therapies for heart failure, it remains a leading cause of morbidity and mortality worldwide, with many patients progressing to advanced stages of the condition. Since the standard treatment for heart failure includes small-molecule drugs targeting G protein-coupled receptors (GPCRs), GPCRs are still considered novel targets for the diagnosis and treatment of cardiovascular diseases. Corticotropin-releasing hormone receptor 2, a highly expressed GPCR in cardiomyocytes, and its ligand, urocortin2 (UCN2), have been reportedly associated with cardiovascular diseases; however, their clinical significance remains unclear. In this study, a UCN2 measurement assay was developed to measure blood UCN2 levels in patients with heart failure. The assay showed that blood UCN2 values indicated a negative relationship with cardiac ejection fraction in 52 patients with heart failure. Blood UCN2 levels were not correlated with brain natriuretic peptide, a standard marker of heart failure, and were higher in patients with cardiomyopathy than in those with heart failure, suggesting that measuring blood UCN2 levels may be a novel test for assessing the pathophysiology of heart failure.

DOI： 10.1038/s41598-025-99509-4

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

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

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

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. Reviewed International coauthorship 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

Authorship：Corresponding author 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

Dynamic upregulation of retinoic acid signal in the early postnatal murine heart promotes cardiomyocyte cell cycle exit and maturation. International journal

Yusuke Fujikawa, Katsuhiro Kato, Kazumasa Unno, Shingo Narita, Yusuke Okuno, Yoshitaka Sato, Mikito Takefuji, Toyoaki Murohara

Scientific reports Vol. 14 ( 1 ) page： 20222 - 20222 2024.8

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

The adult mammalian heart has extremely limited cardiac regenerative capacity. Most cardiomyocytes live in a state of permanent cell-cycle arrest and are unable to re-enter the cycle. Cardiomyocytes switch from cell proliferation to a maturation state during neonatal development. Although several signaling pathways are involved in this transition, the molecular mechanisms by which these inputs coordinately regulate cardiomyocyte maturation are not fully understood. Retinoic acid (RA) plays a pivotal role in development, morphogenesis, and regeneration. Despite the importance of RA signaling in embryo heart development, little is known about its function in the early postnatal period. We found that mRNA expression of aldehyde dehydrogenase 1 family member A2 (Aldh1a2), which encodes the key enzyme for synthesizing all-trans retinoic acid (ATRA) and is an important regulator for RA signaling, was transiently upregulated in neonatal mouse ventricles. Single-cell transcriptome analysis and immunohistochemistry revealed that Aldh1a2 expression was enriched in cardiac fibroblasts during the early postnatal period. Administration of ATRA inhibited cardiomyocyte proliferation in cultured neonatal rat cardiomyocytes and human cardiomyocytes. RNA-seq analysis indicated that cell proliferation-related genes were downregulated in prenatal rat ventricular cardiomyocytes treated with ATRA, while cardiomyocyte maturation-related genes were upregulated. These findings suggest that RA signaling derived from cardiac fibroblasts is one of the key regulators of cardiomyocyte proliferation and maturation during neonatal heart development.

DOI： 10.1038/s41598-024-70918-1

Meflin/ISLR is a marker of adipose stem and progenitor cells in mice and humans that suppresses white adipose tissue remodeling and fibrosis.

Ishihara T, Kato K, Matsumoto K, Tanaka M, Hara A, Shiraki Y, Morisaki H, Urano Y, Ando R, Ito K, Mii S, Esaki N, Furuhashi K, Takefuji M, Suganami T, Murohara T, Enomoto A

Genes to cells : devoted to molecular & cellular mechanisms 2024.8

Language：English Publisher：Genes to Cells

Identifying specific markers of adipose stem and progenitor cells (ASPCs) in vivo is crucial for understanding the biology of white adipose tissues (WAT). PDGFRα-positive perivascular stromal cells represent the best candidates for ASPCs. This cell lineage differentiates into myofibroblasts that contribute to the impairment of WAT function. However, ASPC marker protein(s) that are functionally crucial for maintaining WAT homeostasis are unknown. We previously identified Meflin as a marker of mesenchymal stem cells (MSCs) in bone marrow and tissue-resident perivascular fibroblasts in various tissues. We also demonstrated that Meflin maintains the undifferentiated status of MSCs/fibroblasts. Here, we show that Meflin is expressed in WAT ASPCs. A lineage-tracing experiment showed that Meflin+ ASPCs proliferate in the WAT of obese mice induced by a high-fat diet (HFD), while some of them differentiate into myofibroblasts or mature adipocytes. Meflin knockout mice fed an HFD exhibited a significant fibrotic response as well as increases in adipocyte cell size and the number of crown-like structures in WAT, accompanied by impaired glucose tolerance. These data suggested that Meflin expressed by ASPCs may have a role in reducing disease progression associated with WAT dysfunction.

DOI： 10.1111/gtc.13154

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

How Should Weight Control and Caloric Intervention Be Implemented for Obese Heart Failure Patients?

Okumura T, Hiraiwa H, Takefuji M, Murohara T

Cardiology Vol. 148 ( 2 ) page： 103 - 105 2023

Benefits and Precautions in Using B-Type Natriuretic Peptide　― N-Terminal-Pro-B-Type Natriuretic Peptide Conversion Formula ―

Okumura Takahiro, Hiraiwa Hiroaki, Takefuji Mikito, Murohara Toyoaki

Circulation Journal Vol. 86 ( 12 ) page： 2019 - 2020 2022.11

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

Lixin Fang, Koji Ohashi, Naoya Otaka, Hayato Ogawa, Mizuho Hiramatsu-Ito, Hiroshi Kawanishi, Yasuko K Bando, Rei Shibata, Yuuki Shimizu, Katsuhiro Kato, Tomonobu Takikawa, Yuta Ozaki, Mikito Takefuji, Toyoaki Murohara, Noriyuki Ouchi

Cardiovascular research Vol. 118 ( 6 ) page： 1597 - 1610 2022.5

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

AIMS: Abdominal aortic aneurysm (AAA) is an increasing and life-threatening disease. Obesity contributes to an increased risk of AAA. Omentin is a circulating adipokine, which is downregulated in obese complications. Here, we examined whether omentin could modulate angiotensin (Ang) II-induced AAA formation in apolipoprotein E-knockout (apoE-KO) mice. METHODS AND RESULTS: apoE-KO mice were crossed with transgenic mice expressing the human omentin gene in fat tissue (OMT-Tg mice) to generate apoE-KO/OMT-Tg mice. apoE-KO/OMT-Tg and apoE-KO mice were subjected to continuous Ang II infusion by using osmotic mini pumps. apoE-KO/OMT-Tg mice exhibited a lower incidence of AAA formation and a reduced maximal diameter of AAA compared with apoE-KO mice. apoE-KO/OMT-Tg mice showed attenuated disruption of medial elastic fibres in response to Ang II compared with apoE-KO mice. apoE-KO/OMT-Tg mice also displayed reduced expression levels of matrix metalloproteinase (MMP) 9, MMP2, and pro-inflammatory genes in aortic walls compared with apoE-KO mice. Furthermore, systemic administration of omentin also attenuated AAA formation and disruption of medial elastic fibres in response to Ang II in apoE-KO mice. Treatment of human monocyte-derived macrophages with omentin protein attenuated expression of MMP9 and pro-inflammatory mediators, and MMP9 activation after stimulation with lipopolysaccharide. Treatment of human vascular smooth muscle cells (VSMCs) with omentin protein reduced expression and activation of MMP2 after stimulation with tumour necrosis factor α. Omentin treatment increased phosphorylation levels of Akt in human macrophages and VSMCs. The suppressive effects of omentin on MMP9 and MMP2 expression were reversed by inhibition of integrin-αVβ3/PI3-kinase/Akt signalling in macrophages and VSMCs, respectively. CONCLUSION: These data suggest that omentin acts as an adipokine that can attenuate Ang II-induced development of AAA through suppression of MMP9 and MMP2 expression and inflammatory response in the vascular wall.

DOI： 10.1093/cvr/cvab179

Serum autotaxin as a novel prognostic marker in patients with non-ischaemic dilated cardiomyopathy. Reviewed International journal

Takashi Araki, Takahiro Okumura, Hiroaki Hiraiwa, Takashi Mizutani, Yuki Kimura, Shingo Kazama, Naoki Shibata, Hideo Oishi, Tasuku Kuwayama, Toru Kondo, Ryota Morimoto, Mikito Takefuji, Toyoaki Murohara

ESC heart failure Vol. 9 ( 2 ) page： 1304 - 1313 2022.4

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

AIMS: Autotaxin (ATX) promotes myocardial inflammation, fibrosis, and the subsequent cardiac remodelling through lysophosphatidic acid production. However, the prognostic impact of serum ATX in non-ischaemic dilated cardiomyopathy (NIDCM) has not been clarified. We investigated the prognostic impact of serum ATX in patients with NIDCM. METHODS AND RESULTS: We enrolled 104 patients with NIDCM (49.8 ± 13.4 years, 76 men). We divided the patients into two groups using different cutoffs of median serum ATX levels for men and women: high-ATX group and low-ATX group. Cardiac events were defined as a composite of cardiac death and heart failure resulting in hospitalization. Median ATX level was 203.5 ng/mL for men and 257.0 ng/mL for women. Brain natriuretic peptide levels [224.0 (59.6-689.5) pg/mL vs. 96.5 (40.8-191.5) pg/mL, P = 0.010] were higher in the high-ATX group than low-ATX group, whereas high-sensitivity C-reactive protein and collagen volume fraction levels in endomyocardial biopsy samples were not significantly different between the two groups. Kaplan-Meier survival analysis revealed that the event-free survival rate was significantly lower in the high-ATX group than low-ATX group (log-rank; P = 0.007). Cox proportional hazard analysis revealed that high-ATX was an independent determinant of composite cardiac events. In both sexes, serum ATX levels did not correlate with high-sensitivity C-reactive protein levels and collagen volume fraction but had a weak correlation with brain natriuretic peptide levels (men; spearman's rank: 0.274, P = 0.017, women; spearman's rank: 0.378, P = 0.048). CONCLUSION: High serum ATX levels can be associated with increasing adverse clinical outcomes in patients with NIDCM. These results indicate serum ATX may be a novel biomarker or therapeutic target in NIDCM.

DOI： 10.1002/ehf2.13817

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

G-protein-mediated cellular signaling in heart failure

Takefuji Mikito

Shinzo Vol. 54 ( 2 ) page： 261 - 267 2022.2

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

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

FASEB journal : official publication of the Federation of American Societies for Experimental Biology Vol. 35 ( 12 ) page： e22048 2021.12

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

In the heart, fatty acid is a major energy substrate to fuel contraction under aerobic conditions. Ischemia downregulates fatty acid metabolism to adapt to the limited oxygen supply, making glucose the preferred substrate. However, the mechanism underlying the myocardial metabolic shift during ischemia remains unknown. Here, we show that lipoprotein lipase (LPL) expression in cardiomyocytes, a principal enzyme that converts triglycerides to free fatty acids and glycerol, increases during myocardial infarction (MI). Cardiomyocyte-specific LPL deficiency enhanced cardiac dysfunction and apoptosis following MI. Deficiency of aquaporin 7 (AQP7), a glycerol channel in cardiomyocytes, increased the myocardial infarct size and apoptosis in response to ischemia. Ischemic conditions activated glycerol-3-phosphate dehydrogenase 2 (GPD2), which converts glycerol-3-phosphate into dihydroxyacetone phosphate to facilitate adenosine triphosphate (ATP) synthesis from glycerol. Conversely, GPD2 deficiency exacerbated cardiac dysfunction after acute MI. Moreover, cardiomyocyte-specific LPL deficiency suppressed the effectiveness of peroxisome proliferator-activated receptor alpha (PPARα) agonist treatment for MI-induced cardiac dysfunction. These results suggest that LPL/AQP7/GPD2-mediated glycerol metabolism plays an important role in preventing myocardial ischemia-related damage.

DOI： 10.1096/fj.202100882R

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

Hideo Oishi, Takahiro Okumura, Koji Ohashi, Yuki Kimura, Shingo Kazama, Naoki Shibata, Yoshihito Arao, Hiroo Kato, Tasuku Kuwayama, Shogo Yamaguchi, Minako Tatsumi, Toru Kondo, Hiroaki Hiraiwa, Ryota Morimoto, Mikito Takefuji, Noriyuki Ouchi, Toyoaki Murohara

Journal of cardiology Vol. 78 ( 6 ) page： 524 - 532 2021.12

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

BACKGROUND: Follistatin-like 1 (FSTL1) is a myocyte-secreted glycoprotein that could play a role in myocardial maintenance in response to harmful stimuli. We investigated the association between serum FSTL1 levels, especially focused on transcardiac gradient and the hemodynamics, to explore the prognostic impact of FSTL1 levels in patients with dilated cardiomyopathy (DCM). METHODS: Thirty-two ambulatory patients with DCM (23 men; mean age 59 years) were prospectively enrolled. Blood samples were simultaneously collected from the aortic root (Ao), coronary sinus (CS), as well as from the peripheral vein during cardiac catheterization in stable conditions. The transcardiac gradient of FSTL1 was calculated by the difference between serum FSTL1 levels of CS and Ao (FSTL1CS-Ao). Patients were divided into two groups based on the median of FSTL1CS-Ao: Low FSTL1CS-Ao group, <0 ng/mL; High FSTL1CS-Ao group, ≥0 ng/mL. Cardiac events were defined as a composite of cardiac deaths and hospitalizations for worsening heart failure. RESULTS: Mean left ventricular ejection fraction and median plasma B-type natriuretic peptide levels were 30.9% and 92.3 pg/mL, respectively. FSTL1CS-Ao was negatively correlated with pulmonary capillary wedge pressure (r = -0.400, p = 0.023). Kaplan-Meier survival analysis showed that event-free survival rate was significantly lower in the Low FSTL1CS-Ao group than in the High FSTL1CS-Ao group (p = 0.013). Cox regression analyses revealed that the transcardiac gradient of FSTL1 was an independent predictor for cardiac events. Receiver operating characteristic curve analysis showed that the cut-off value of FSTL1CS-Ao for the prediction of cardiac events was -4.09 ng/mL with sensitivity of 82% and specificity of 86% (area under the curve, 0.87). CONCLUSIONS: Fifty percent of patients had negative transcardiac gradient of FSTL1. Reduced transcardiac gradient of FSTL1 might be a novel prognostic predictor in DCM patients with impaired hemodynamics.

DOI： 10.1016/j.jjcc.2021.07.005

Serum autotaxin level predicts future cardiac events in patients with dilated cardiomyopathy Reviewed

Araki, T; Okumura, T; Mizutani, T; Kimura, Y; Kazama, S; Shibata, N; Oishi, H; Kuwayama, T; Hiraiwa, H; Kondo, T; Morimoto, R; Takefuji, M; Murohara, T

EUROPEAN HEART JOURNAL Vol. 42 page： 1730 - 1730 2021.10

Adverse Effect of Circadian Rhythm Disorder on Reparative Angiogenesis in Hind Limb Ischemia. International journal

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

Journal of the American Heart Association Vol. 10 ( 16 ) page： e020896 2021.8

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

Background Circadian rhythm disorders, often seen in modern lifestyles, are a major social health concern. The aim of this study was to examine whether circadian rhythm disorders would influence angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia. Methods and Results A jet-lag model was established in C57BL/6J mice using a light-controlled isolation box. Control mice were kept at a light/dark 12:12 (12-hour light and 12-hour dark) condition. Concentrations of plasma vascular endothelial growth factor and circulating endothelial progenitor cells in control mice formed a circadian rhythm, which was diminished in the jet-lag model (P<0.05). The jet-lag condition deteriorated tissue capillary formation (P<0.001) and tissue blood perfusion recovery (P<0.01) in hind limb ischemia, which was associated with downregulation of vascular endothelial growth factor expression in local ischemic tissue and in the plasma. Although the expression of clock genes (ie, Clock, Bmal1, and Cry) in local tissues was upregulated after ischemic injury, the expression levels of cryptochrome (Cry) 1 and Cry2 were inhibited by the jet-lag condition. Next, Cry1 and Cry2 double-knockout mice were examined for blood perfusion recoveries and a reparative angiogenesis. Cry1 and Cry2 double-knockout mice revealed suppressed capillary density (P<0.001) and suppressed tissue blood perfusion recovery (P<0.05) in the hind limb ischemia model. Moreover, knockdown of CRY1/2 in human umbilical vein endothelial cells was accompanied by increased expression of WEE1 and decreased expression of HOXC5. This was associated with decreased proliferative capacity, migration ability, and tube formation ability of human umbilical vein endothelial cells, respectively, leading to impairment of angiogenesis. Conclusions Our data suggest that circadian rhythm disorder deteriorates reparative ischemia-induced angiogenesis and that maintenance of circadian rhythm plays an important role in angiogenesis.

DOI： 10.1161/JAHA.121.020896

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