SIRT6 Protects Smooth Muscle Cells From Senescence and Reduces Atherosclerosis.
SIRT6 Protects Smooth Muscle Cells From Senescence and Reduces Atherosclerosis.
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DOI：
10.1161/circresaha.120.318353
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发表时间：
2021-02-19
影响因子：
20.1
通讯作者：
Bennett MR
中科院分区：
文献类型：
--
作者：
Grootaert MOJ;Finigan A;Figg NL;Uryga AK;Bennett MR
补充数字内容可在文本中找到。血管平滑肌细胞（VSMC）衰老促进动脉粥样硬化和斑块不稳定的特征，部分是通过脂质介导的氧化DNA损伤和端粒功能障碍。SIRT 6（Sirtuin 6）是一种核脱乙酰酶，参与DNA损伤反应信号传导、炎症和代谢;然而，其在调节VSMC衰老和动脉粥样硬化中的作用尚不清楚。我们研究了SIRT 6在人VSMC中的表达，SIRT 6激活的作用、调节和下游通路，以及VSMC SIRT 6如何调节动脉粥样硬化形成。与健康主动脉VSMCs相比，SIRT 6蛋白而非mRNA表达在人和小鼠动脉粥样硬化斑块中的VSMCs中，以及来自斑块或经历复制或棕榈酸诱导衰老的人VSMCs中显著降低。泛素连接酶CHIP（HSC 70相互作用蛋白的C末端）促进SIRT 6的稳定性，但CHIP的表达在人类和小鼠斑块VSMCs和棕榈酸以p38-和c-Jun N-末端激酶依赖的方式减少。SIRT 6与端粒结合，而使用shRNA或脱乙酰酶失活突变体（SIRT 6 H133 Y）抑制SIRT 6缩短了人VSMC寿命并诱导衰老，与端粒H3 K9（组蛋白H3赖氨酸9）过度乙酰化和53 BP 1（p53结合蛋白1）结合相关，表明端粒损伤。相反，SIRT 6过表达保留端粒完整性，延迟细胞衰老，并减少炎性细胞因子表达和与衰老相关的VSMC代谢变化。SIRT 6，而不是SIRT 6 H133 Y，促进小鼠VSMCs的增殖和寿命，并防止衰老相关的代谢变化。产生仅在VSMC中过表达SIRT 6或SIRT 6 H133 Y的ApoE−/−（载脂蛋白E）小鼠。与同窝对照相比，SM 22 α-hSIRT 6/ApoE−/−小鼠的动脉粥样硬化、衰老和炎症标志物减少，而SM 22 α-hSIRT 6 H133 Y/ApoE−/−小鼠的斑块显示出斑块不稳定性增加的特征。SIRT 6蛋白表达在人类和小鼠斑块VSMC中减少，并受到CHIP的正调控。SIRT 6调节端粒维持和VSMC寿命并抑制动脉粥样硬化形成，所有这些都依赖于其脱乙酰酶活性。我们的数据表明，内源性SIRT 6脱乙酰酶是一个重要的和未被认识的抑制剂VSMC衰老和动脉粥样硬化。
Supplemental Digital Content is available in the text. Vascular smooth muscle cell (VSMC) senescence promotes atherosclerosis and features of plaque instability, in part, through lipid-mediated oxidative DNA damage and telomere dysfunction. SIRT6 (Sirtuin 6) is a nuclear deacetylase involved in DNA damage response signaling, inflammation, and metabolism; however, its role in regulating VSMC senescence and atherosclerosis is unclear. We examined SIRT6 expression in human VSMCs, the role, regulation, and downstream pathways activated by SIRT6, and how VSMC SIRT6 regulates atherogenesis. SIRT6 protein, but not mRNA, expression was markedly reduced in VSMCs in human and mouse atherosclerotic plaques, and in human VSMCs derived from plaques or undergoing replicative or palmitate-induced senescence versus healthy aortic VSMCs. The ubiquitin ligase CHIP (C terminus of HSC70-interacting protein) promoted SIRT6 stability, but CHIP expression was reduced in human and mouse plaque VSMCs and by palmitate in a p38- and c-Jun N-terminal kinase-dependent manner. SIRT6 bound to telomeres, while SIRT6 inhibition using shRNA or a deacetylase-inactive mutant (SIRT6H133Y) shortened human VSMC lifespan and induced senescence, associated with telomeric H3K9 (histone H3 lysine 9) hyperacetylation and 53BP1 (p53 binding protein 1) binding, indicative of telomere damage. In contrast, SIRT6 overexpression preserved telomere integrity, delayed cellular senescence, and reduced inflammatory cytokine expression and changes in VSMC metabolism associated with senescence. SIRT6, but not SIRT6H133Y, promoted proliferation and lifespan of mouse VSMCs, and prevented senescence-associated metabolic changes. ApoE−/− (apolipoprotein E) mice were generated that overexpress SIRT6 or SIRT6H133Y in VSMCs only. SM22α-hSIRT6/ApoE−/− mice had reduced atherosclerosis, markers of senescence and inflammation compared with littermate controls, while plaques of SM22α-hSIRT6H133Y/ApoE−/− mice showed increased features of plaque instability. SIRT6 protein expression is reduced in human and mouse plaque VSMCs and is positively regulated by CHIP. SIRT6 regulates telomere maintenance and VSMC lifespan and inhibits atherogenesis, all dependent on its deacetylase activity. Our data show that endogenous SIRT6 deacetylase is an important and unrecognized inhibitor of VSMC senescence and atherosclerosis.