Division of Cardiovascular Medicine, University of Cambridge, United Kingdom.
Circ Res. 2021 Feb 19;128(4):474-491. doi: 10.1161/CIRCRESAHA.120.318353. Epub 2020 Dec 22.
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 (SIRT6) 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 SIRT6, promoted proliferation and lifespan of mouse VSMCs, and prevented senescence-associated metabolic changes. ApoE (apolipoprotein E) mice were generated that overexpress SIRT6 or SIRT6 in VSMCs only. SM22α-hSIRT6/ApoE mice had reduced atherosclerosis, markers of senescence and inflammation compared with littermate controls, while plaques of SM22α-hSIRT6/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.
血管平滑肌细胞（VSMC）衰老会促进动脉粥样硬化和斑块不稳定的特征，部分原因是脂质介导的氧化 DNA 损伤和端粒功能障碍。SIRT6（Sirtuin 6）是一种参与 DNA 损伤反应信号转导、炎症和代谢的核去乙酰化酶；然而，其在调节 VSMC 衰老和动脉粥样硬化中的作用尚不清楚。
我们检测了人类 VSMC 中的 SIRT6 表达，研究了 SIRT6 的作用、调节以及激活的下游途径，以及 VSMC SIRT6 如何调节动脉粥样硬化形成。
与健康主动脉 VSMC 相比，人源和鼠源动脉粥样硬化斑块中的 VSMC 以及源自斑块或经历复制或软脂酸诱导衰老的人源 VSMC 中，SIRT6 蛋白而非 mRNA 的表达明显降低。泛素连接酶 CHIP（HSC70 相互作用蛋白 C 端）促进 SIRT6 稳定性，但人源和鼠源斑块 VSMC 中的 CHIP 表达以及软脂酸诱导的 p38 和 c-Jun N 末端激酶依赖性表达降低。SIRT6 与端粒结合，而使用 shRNA 或去乙酰化酶失活突变体（SIRT6）抑制 SIRT6 会缩短人源 VSMC 的寿命并诱导衰老，与端粒 H3K9（组蛋白 H3 赖氨酸 9）超乙酰化和 53BP1（p53 结合蛋白 1）结合相关，表明端粒损伤。相比之下，SIRT6 过表达可保持端粒完整性，延迟细胞衰老，并降低与衰老相关的炎症细胞因子表达和 VSMC 代谢变化。SIRT6 而非 SIRT6 可促进鼠源 VSMC 的增殖和寿命，并预防衰老相关的代谢变化。仅在 VSMCs 中过表达 SIRT6 或 SIRT6 的 ApoE（载脂蛋白 E）小鼠被生成。SM22α-hSIRT6/ApoE 小鼠与同窝对照相比，动脉粥样硬化、衰老和炎症标志物减少，而 SM22α-hSIRT6/ApoE 小鼠的斑块显示出增加的斑块不稳定特征。
人源和鼠源斑块 VSMC 中的 SIRT6 蛋白表达降低，且受 CHIP 正向调节。SIRT6 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去乙酰化酶活性。我们的数据表明，内源性 SIRT6 去乙酰化酶是 VSMC 衰老和动脉粥样硬化的一个重要且未被认识的抑制剂。
