Qiu Lin, Yi Shaolei, Yu Tingting, Hao Yan
Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Front Cardiovasc Med. 2021 May 21;8:675647. doi: 10.3389/fcvm.2021.675647. eCollection 2021.
Sirtuin3 (Sirt3) is a histone deacetylase involved in the regulation of many cellular processes. Sirt3 deficiency is known to increase oxidative stress. Reactive oxygen species (ROS) promote degradation of the extracellular matrix and vascular smooth muscle cell (VSMC) apoptosis. Reducing oxidative stress by Sirt3 overexpression could have therapeutic potential for limiting thoracic aortic dissection (TAD) development. We hypothesized that Sirt3 deficiency could increase the risk for TAD by decreasing ROS elimination and that Sirt3 overexpression (Sirt3) could provide an alternative option for TAD treatment. Mice with TAD had significantly lower Sirt3 expression than normal subjects. Sirt3 KO mice exhibit significantly increased TAD incidence rate and increased aortic diameters. Moreover, Sirt3 overexpression reduced Ang II-induced ROS production, NF-kB activation, and apoptosis in human aortic smooth muscle cells (HASMCs). Sirt3 overexpression attenuated aneurysm formation and decreased aortic expansion. In conclusion, our data showed that Sirt3 deficiency increases susceptibility to TAD formation by attenuating anti-ROS effects and increasing VSMC apoptosis and vascular inflammation.
沉默调节蛋白3（Sirt3）是一种参与多种细胞过程调控的组蛋白去乙酰化酶。已知Sirt3缺乏会增加氧化应激。活性氧（ROS）会促进细胞外基质降解和血管平滑肌细胞（VSMC）凋亡。通过过表达Sirt3来降低氧化应激可能对限制胸主动脉夹层（TAD）的发展具有治疗潜力。我们推测，Sirt3缺乏可能通过减少ROS清除而增加TAD风险，而过表达Sirt3（Sirt3）可为TAD治疗提供另一种选择。患有TAD的小鼠的Sirt3表达明显低于正常受试者。Sirt3基因敲除小鼠的TAD发病率显著增加，主动脉直径增大。此外，Sirt3过表达减少了血管紧张素II诱导的人主动脉平滑肌细胞（HASMCs）中的ROS产生、NF-κB激活和凋亡。Sirt3过表达减弱了动脉瘤形成并减少了主动脉扩张。总之，我们的数据表明，Sirt3缺乏通过减弱抗ROS作用、增加VSMC凋亡和血管炎症而增加了TAD形成的易感性。
