Faculty Profiles - OHASHI, Koji

Papers - OHASHI, Koji

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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Papers - OHASHI, Koji