Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice
Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice
复制标题
DOI：
10.1093/cvr/cvn224
复制
发表时间：
2008-11-01
影响因子：
10.8
通讯作者：
Liang, Chih-chuan
中科院分区：
文献类型：
--
作者：
Zhang, Qing-jun;Wang, Zhao;Liang, Chih-chuan
目的 危险的环境和遗传因素会损害内皮细胞，诱发动脉粥样硬化性血管疾病。最近的研究表明，III 类脱乙酰酶 SIRT1 可能通过新的抗氧化机制促进细胞存活。本研究验证了在内皮细胞中特异性过度表达的 SIRT1 具有动脉粥样硬化保护作用的假设。 方法和结果 利用人脐静脉内皮细胞 (HUVEC) 研究氧化低密度脂蛋白 (LDL) 对 SIRT1 表达的影响。内皮细胞特异性 SIRT1 转基因 (SIRT1-Tg) 小鼠用于研究 SIRT1 对主动脉血管张力的影响。 SIRT1-Tg 小鼠与载脂蛋白 E 缺失 (apoE(-/-)) 小鼠杂交，获得 SIRT1-Tg/apoE(-/-) 小鼠，用于分析 SIRT1 内皮过度表达的情况下的动脉粥样硬化形成。通过氧化 LDL 处理，HUVEC 中的 SIRT1 表达增加。腺病毒介导的 SIRT1 过度表达可保护 HUVEC 凋亡。热量限制增加了小鼠主动脉中 SIRT1 的表达，而高脂肪饮食则减少了 SIRT1 的表达。在 SIRT1-Tg 小鼠中，与野生型同窝小鼠相比，高脂肪引起的内皮依赖性血管舒张损伤得到改善。 SIRT1-Tg 小鼠中主动脉内皮一氧化氮合酶表达上调。与apoE(-/-)对照相比，SIRT1-Tg/apoE(-/-)小鼠的动脉粥样硬化病变较少，且不影响血脂和血糖水平。结论这些结果表明内皮特异性SIRT1过表达可能通过改善内皮细胞存活和功能来抑制动脉粥样硬化形成。
Aims Hazardous environmental and genetic factors can damage endothelial cells to induce atherosclerotic vascular disease. Recent studies suggest that class III deacetylase SIRT1 may promote cell survival via novel antioxidative mechanisms. The current study tested the hypothesis that SIRT1, specifically overexpressed in the endothelium, is atheroprotective.Methods and results Human umbilical vein endothelial cells (HUVECs) were used to study the effects of oxidized low-density lipoprotein (LDL) on SIRT1 expression. Endothelial cell-specific SIRT1 transgenic (SIRT1-Tg) mice were used to study the effects of SIRT1 on aortic vascular tone. SIRT1-Tg mice were crossed with apolipoprotein E null (apoE(-/-)) mice to obtain SIRT1-Tg/apoE(-/-) mice for the analysis of atherogenesis in the presence of endothelial overexpression of SIRT1. SIRT1 expression in HUVECs was increased by the treatment with oxidative LDL. Adenoviral-mediated overexpression of SIRT1 was protective of apoptosis of HUVECs. Calorie restriction increased, whereas high-fat diet decreased, the SIRT1 expression in mouse aortas. In SIRT1-Tg mice, high fat-induced impairment in endothelium-dependent vasorelaxation was improved compared with that of wild-type littermates. This was accompanied by an upregualtion of aortic endothelial nitric oxide synthase expression in the SIRT1-Tg mice. The SIRT1-Tg/apoE(-/-) mice had less atherosclerotic lesions compared with apoE(-/-) controls, without affecting blood lipids and glucose levels.Conclusion These results suggest that endothelium-specific SIRT1 overexpression likely suppresses atherogenesis via improving endothelial cell survival and function.