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(Hypertension. 2006;47:265.)
© 2006 American Heart Association, Inc.

Original Articles

Activation of AMP-Activated Protein Kinase Enhances Angiotensin II–Induced Proliferation in Cardiac Fibroblasts

Yoshiyuki Hattori; Kazumi Akimoto; Toshio Nishikimi; Hiroaki Matsuoka; Kikuo Kasai

From the Department of Endocrinology and Metabolism (Y.H., K.K.), Department of Hypertension and Cardiorenal Medicine (T.N., H.M.), and the Laboratory of Molecular and Cellular Biology (K.A.), Dokkyo University School of Medicine, Mibu, Tochigi, Japan.

Correspondence to Yoshiyuki Hattori, Department of Endocrinology and Metabolism, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. E-mail yhattori{at}dokkyomed.ac.jp

AMP-activated kinase (AMPK) is a highly conserved heterotrimeric kinase that functions as a metabolic regulator of cellular enzymes involved in carbohydrate and fat metabolism, which regulate ATP conservation and synthesis. Here, we investigated whether AMPK signaling has a role in the regulation of angiotensin II (Ang II)–induced proliferation in rat cardiac fibroblasts. Aminoimidazole-4-carboxamide-1-ß-ribofuranoside (AICAR) activated AMPK in rat cardiac fibroblasts and increased Ang II–induced extracellular signal–regulated kinase 1/2 phosphorylation and activity. AICAR also increased Ang II–induced c-fos mRNA expression in the cells. [³H]-thymidine and [³H]-proline incorporation by cardiac fibroblasts treated with Ang II was enhanced when the cells were pretreated with AICAR. Inhibition of AMPK by small interfering RNA for AMPK1 suppressed Ang II–induced extracellular signal–regulated kinase activity, c-fos mRNA expression, and cell proliferation. Treatment of rats with AICAR (1 mg/g body weight per day) for 1 week significantly enhanced Ang II–induced hypertrophy of the myocardium. Our findings indicate that AMPK works as a stimulator of the Ang II–induced proliferative pathway in cardiac fibroblasts. Inhibition of AMPK signaling might serve as a new therapeutic target of remodeling of the hypertrophic myocardium.

Key Words: cardiac function • angiotensin • hypertrophy • signal transduction

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