Faculty Profiles - OHASHI, Koji

Papers - OHASHI, Koji

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

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

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

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

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

DOI： 10.1038/hr.2011.130

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

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

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

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

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

DOI： 10.1073/pnas.1108559108

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

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

The Journal of Biological Chemistry 2011.10

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

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

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

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

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

DOI： 10.1074/jbc.M111.277319

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

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

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

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

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

DOI： 10.1074/jbc.M111.245985

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

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

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

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

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

DOI： 10.1152/ajpheart.00428.2011

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Adiponectin and hypertension. Reviewed

Ohashi K, Ouchi N, Matsuzawa Y.

American Journal of Hypertensions 2011.3

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

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

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

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

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

DOI： 10.1159/000330178

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

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

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

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

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

DOI： 10.1152/ajpendo.00284.2010

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

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

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

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

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

DOI： 10.1016/j.yjmcc.2010.02.021

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

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

Science 2010.7

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

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

The Journal of Biological Chemistry 2010.7

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

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

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

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

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

DOI： 10.1161/CIRCRESAHA.109.209007

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DIP2A Functions as a FSTL1 Receptor Reviewed

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

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

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

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

DOI： 10.1074/jbc.M109.069468

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

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

The Journal of Biological Chemistry 2010.2

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

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

Arteriosclerosis, Thrombosis, and Vascular Biology 2010.1

Adiponectin Deficiency, Diastolic Dysfunction, and Diastolic Heart Failure Reviewed

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

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

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

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

DOI： 10.1210/en.2009-0806

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

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

Circulation Research 2009.5

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

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

Molecular and Cellular Biology 2009.4

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

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

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

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

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

DOI： 10.1074/jbc.M803440200

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Papers - OHASHI, Koji