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(Circulation Research. 2005;97:837.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Adenosine Monophosphate-Activated Protein Kinase Suppresses Vascular Smooth Muscle Cell Proliferation Through the Inhibition of Cell Cycle Progression

Motoyuki Igata^*, Hiroyuki Motoshima^*, Kaku Tsuruzoe, Kanou Kojima, Takeshi Matsumura, Tatsuya Kondo, Tetsuya Taguchi, Kazuhiko Nakamaru, Miyuki Yano, Daisuke Kukidome, Kazuya Matsumoto, Tetsushi Toyonaga, Tomoichiro Asano, Takeshi Nishikawa, Eiichi Araki

From the Department of Metabolic Medicine (M.I., H.M., K.T., K.K., T.M., T.K., T. Taguchi, K.N., M.Y., D.K., K.M., T. Toyonaga, T.N., E.A.), Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, and the Department of Physiological Chemistry and Metabolism (T.A.), Graduate School of Medicine, University of Tokyo, Japan.

Correspondence to Hiroyuki Motoshima, Department of Metabolic Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8554, Japan. E-mail hmoto{at}gpo.kumamoto-u.ac.jp

Vascular smooth muscle cell (VSMC) proliferation is a critical event in the development and progression of vascular diseases, including atherosclerosis. We investigated whether the activation of adenosine monophosphate-activated protein kinase (AMPK) could suppress VSMC proliferation and inhibit cell cycle progression. Treatment of human aortic smooth muscle cells (HASMCs) or isolated rabbit aortas with the AMPK activator 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) induced phosphorylation of AMPK and acetyl Co-A carboxylase. AICAR significantly inhibited HASMC proliferation induced by both platelet-derived growth factor-BB (PDGF-BB) and fetal calf serum (FCS). Treatment with AICAR inhibited the phosphorylation of retinoblastoma gene product (Rb) induced by PDGF-BB or FCS, and increased the expression of cyclin-dependent kinase inhibitor p21^CIP but not that of p27^KIP. Pharmacological inhibition of AMPK or overexpression of dominant negative-AMPK inhibited both the suppressive effect of AICAR on cell proliferation and the phosphorylation of Rb, suggesting that the effect of AICAR is mediated through the activation of AMPK. Cell cycle analysis in HASMCs showed that AICAR significantly increased cell population in G0/G1-phase and reduced that in S- and G2/M-phase, suggesting AICAR induced cell cycle arrest. AICAR increased both p53 protein and Ser-15 phosphorylated p53 in HASMCs, which were blocked by inhibition of AMPK. In isolated rabbit aortas, AICAR also increased Ser-15 phosphorylation and protein expression of p53 and inhibited Rb phosphorylation induced by FCS. These data suggest for the first time that AMPK suppresses VSMC proliferation via cell cycle regulation by p53 upregulation. Therefore, AMPK activation in VSMCs may be a therapoietic target for the prevention of vascular diseases.

Key Words: AMP-activated protein kinase • cell cycle arrest • p53 • p21 • AICAR

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