Faculty Profiles - OHASHI, Koji

Papers - OHASHI, Koji

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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

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PubMed

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

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Scopus

PubMed

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

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PubMed

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

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PubMed

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

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PubMed

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

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PubMed

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

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PubMed

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

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PubMed

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

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PubMed

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

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PubMed

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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PubMed

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Papers - OHASHI, Koji