Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway
Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway
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DOI：
10.1161/circulationaha.106.626606
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发表时间：
2006-08-29
期刊：
影响因子：
37.8
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Kunieda, Takeshige;Minamino, Tohru;Komuro, Issei
背景-血管紧张素II（AngII）已被报道参与多种人类疾病包括动脉粥样硬化的发病机制，并且已显示抑制AngII活性可降低心血管疾病的发病率和死亡率。我们以前已经证明，血管细胞衰老有助于动脉粥样硬化的发病机制，然而，血管紧张素II对血管细胞衰老的影响还没有被examined.Methods和Results-Ang II显着诱导人血管平滑肌细胞（VSMCs）通过p53/p21依赖的途径在体外过早衰老。抑制这一途径有效地抑制了促炎细胞因子的诱导和血管紧张素II的VSMCs的过早衰老。血管紧张素Ⅱ还显着增加了衰老的VSMCs的数量，并诱导促炎分子和p21在小鼠动脉粥样硬化模型的表达。p21的缺失显著改善了Ang II对促炎分子的诱导，从而阻止了动脉粥样硬化的发展。用野生型细胞替换p21缺陷骨髓细胞对p21缺陷对Ang II诱导的动脉粥样硬化形成的保护作用几乎没有影响。结论我们证明了Ang II通过诱导VSMCs在体外和体内的过早衰老来促进血管炎症。我们的研究结果表明，在动脉粥样硬化的发病机制中的VSMCs的p21依赖性的过早衰老的关键作用。
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.