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(Circulation. 2006;114:953-960.)
© 2006 American Heart Association, Inc.

Vascular Medicine

Angiotensin II Induces Premature Senescence of Vascular Smooth Muscle Cells and Accelerates the Development of Atherosclerosis via a p21-Dependent Pathway

Takeshige Kunieda, MD, PhD^*; Tohru Minamino, MD, PhD^*; Jun-ichiro Nishi, MD; Kaoru Tateno, MD, PhD; Tomomi Oyama, MD, PhD; Taro Katsuno; Hideyuki Miyauchi, MD, PhD; Masayuki Orimo, MD; Sho Okada, MD; Masayuki Takamura, MD, PhD; Toshio Nagai, MD, PhD; Shuichi Kaneko, MD, PhD; Issei Komuro, MD, PhD

From the Department of Cardiovascular Science and Medicine (T. Kunieda, T. M., J.-i.N., K.T., T.O., T. Katsuno, H.M., M.O., S.O., T.N., I.K.), Chiba University Graduate School of Medicine, Chiba, Japan, and Department of Gastroenterology (M.T., S.K.), Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.

Correspondence to Issei Komuro, MD, PhD, Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail komuro-tky{at}umin.ac.jp

Received March 13, 2006; revision received July 5, 2006; accepted July 7, 2006.

Background— Angiotensin II (Ang II) has been reported to contribute to the pathogenesis of various human diseases including atherosclerosis, and inhibition of Ang II activity has been shown to reduce the morbidity and mortality of cardiovascular diseases. We have previously demonstrated that vascular cell senescence contributes to the pathogenesis of atherosclerosis; however, the effects of Ang II on vascular cell senescence have not been examined.

Methods and Results— Ang II significantly induced premature senescence of human vascular smooth muscle cells (VSMCs) via the p53/p21-dependent pathway in vitro. Inhibition of this pathway effectively suppressed induction of proinflammatory cytokines and premature senescence of VSMCs by Ang II. Ang II also significantly increased the number of senescent VSMCs and induced the expression of proinflammatory molecules and of p21 in a mouse model of atherosclerosis. Loss of p21 markedly ameliorated the induction of proinflammatory molecules by Ang II, thereby preventing the development of atherosclerosis. Replacement of p21-deficient bone marrow cells with wild-type cells had little influence on the protective effect of p21 deficiency against the progression of atherogenesis induced by Ang II.

Conclusions— We demonstrated that Ang II promotes vascular inflammation by inducing premature senescence of VSMCs both in vitro and in vivo. Our results suggest a critical role of p21-dependent premature senescence of VSMCs in the pathogenesis of atherosclerosis.

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