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(Hypertension. 2008;52:573.)
© 2008 American Heart Association, Inc.

Original Articles

Olmesartan Prevents Cardiovascular Injury and Hepatic Steatosis in Obesity and Diabetes, Accompanied by Apoptosis Signal Regulating Kinase-1 Inhibition

Eiichiro Yamamoto; Yi-Fei Dong; Keiichiro Kataoka; Takuro Yamashita; Yoshiko Tokutomi; Shinji Matsuba; Hidenori Ichijo; Hisao Ogawa; Shokei Kim-Mitsuyama

From the Departments of Pharmacology and Molecular Therapeutics (E.Y., Y-F.D., K.K., T.Y., Y.T., S.M., S.K-M.) and Cardiovascular Medicine (H.O.), Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; and the Laboratory of Cell Signaling (H.I.), Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.

Correspondence to Shokei Kim-Mitsuyama, Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjyo, Kumamoto 860-8556, Japan. E-mail kimmitsu{at}gpo.kumamoto-u.ac.jp

Dietary obesity is associated with type 2 diabetes and cardiovascular diseases, although the underlying mechanism is unknown. This study was undertaken to elucidate the role of angiotensin II and apoptosis signal regulating kinase-1 (ASK1) in obesity/diabetes-associated cardiovascular complications and hepatic steatosis. Mice fed a high-fat diet were treated with olmesartan, an angiotensin II type 1 receptor blocker, to elucidate the role of angiotensin II in diabetic mice. Treatment of mice fed a high-fat diet with olmesartan markedly suppressed cardiac inflammation and fibrosis, as well as vascular endothelial dysfunction and remodeling, induced by obesity/diabetes. Moreover, olmesartan suppressed the disruption of the vascular endothelial NO synthase dimer in diabetic mice. Olmesartan also significantly prevented hepatic steatosis and fibrosis in diabetic mice. These beneficial effects of olmesartan on diabetic mice were associated with the attenuation of ASK1 activation in these mice. ASK1-deficient mice and wild-type mice were compared, regarding the effects of a high-fat diet. A comparison between ASK1-deficient and wild-type mice showed that ASK1 deficiency attenuated cardiac inflammation and fibrosis, as well as vascular endothelial dysfunction and remodeling induced by obesity/diabetes. The amelioration of vascular endothelial impairment by ASK1 deficiency was attributed to the prevention of endothelial NO synthase dimer disruption. ASK1 deficiency also significantly lessened hepatic steatosis in diabetic mice. In conclusion, our work provided the evidence that ASK1 is significantly activated in diet-induced diabetic mice and contributes to cardiovascular diseases and hepatic steatosis in diabetic mice. Moreover, the beneficial effects of angiotensin II inhibition on dietary diabetic mice seem to be mediated by the inhibition of ASK1 activation.

Key Words: diabetes • obesity • angiotensin • ASK1 • reactive oxygen species • vascular endothelial function • cardiac injury

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