Age-Associated Sirtuin 1 Reduction in Vascular Smooth Muscle Links Vascular Senescence and Inflammation to Abdominal Aortic Aneurysm.
Age-Associated Sirtuin 1 Reduction in Vascular Smooth Muscle Links Vascular Senescence and Inflammation to Abdominal Aortic Aneurysm.
复制标题
年龄相关的 Sirtuin 1 血管平滑肌减少与血管衰老和炎症与腹主动脉瘤有关
DOI：
10.1161/circresaha.116.308895
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发表时间：
2016-10-28
影响因子：
20.1
通讯作者：
Liu DP
中科院分区：
文献类型：
--
作者：
Chen HZ;Wang F;Gao P;Pei JF;Liu Y;Xu TT;Tang X;Fu WY;Lu J;Yan YF;Wang XM;Han L;Zhang ZQ;Zhang R;Zou MH;Liu DP
腹主动脉瘤（AAA）的不受控制的生长是一种危及生命的血管疾病，没有有效的药物治疗。男性AAA发病率随年龄增长而显著增加。然而，衰老使个体易患AAAs的分子机制仍然未知。在这项研究中，我们研究了SIRT 1（Sirtuin 1），一种III类组蛋白去乙酰化酶，在AAA形成中的作用以及连接血管衰老和炎症的潜在机制。SIRT 1的表达和活性在人AAA样品中显著降低。在老年小鼠肾上腺髓质中，血管平滑肌细胞中的SIRT 1显著下调，其中血管紧张素II诱导的AAAs显著升高。此外，血管平滑肌细胞特异性敲除SIRT 1可加速血管紧张素II诱导的AAA形成和破裂以及AAA相关的病理变化，而血管平滑肌细胞特异性过表达SIRT 1可抑制Apoe−/−小鼠中血管紧张素II诱导的AAA形成和进展。此外，SIRT 1对AAA形成的抑制作用也在氯化钙（CaCl 2）诱导的AAA模型中得到证实。从机制上讲，SIRT 1的减少显示出增加血管细胞衰老和上调p21表达，以及增强血管炎症。值得注意的是，通过SIRT 1抑制p21依赖性血管细胞衰老阻断了血管紧张素II诱导的核因子-κB与单核细胞趋化蛋白-1启动子的结合，并抑制其表达。这些发现提供了证据表明SIRT 1减少将血管衰老和炎症与AAA联系起来，并且血管平滑肌细胞中的SIRT 1为预防AAA形成提供了治疗靶点。
Uncontrolled growth of abdominal aortic aneurysms (AAAs) is a life-threatening vascular disease without an effective pharmaceutical treatment. AAA incidence dramatically increases with advancing age in men. However, the molecular mechanisms by which aging predisposes individuals to AAAs remain unknown. In this study, we investigated the role of SIRT1 (Sirtuin 1), a class III histone deacetylase, in AAA formation and the underlying mechanisms linking vascular senescence and inflammation. The expression and activity of SIRT1 were significantly decreased in human AAA samples. SIRT1 in vascular smooth muscle cells was remarkably downregulated in the suprarenal aortas of aged mice, in which AAAs induced by angiotensin II infusion were significantly elevated. Moreover, vascular smooth muscle cell–specific knockout of SIRT1 accelerated angiotensin II–induced formation and rupture of AAAs and AAA-related pathological changes, whereas vascular smooth muscle cell–specific overexpression of SIRT1 suppressed angiotensin II–induced AAA formation and progression in Apoe−/− mice. Furthermore, the inhibitory effect of SIRT1 on AAA formation was also proved in a calcium chloride (CaCl2)–induced AAA model. Mechanistically, the reduction of SIRT1 was shown to increase vascular cell senescence and upregulate p21 expression, as well as enhance vascular inflammation. Notably, inhibition of p21-dependent vascular cell senescence by SIRT1 blocked angiotensin II–induced nuclear factor-κB binding on the promoter of monocyte chemoattractant protein-1 and inhibited its expression. These findings provide evidence that SIRT1 reduction links vascular senescence and inflammation to AAAs and that SIRT1 in vascular smooth muscle cells provides a therapeutic target for the prevention of AAA formation.