Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, University of South China, Hengyang, Hunan, 421001, China; Department of Pathology & Pathophysiology, Hunan University of Medicine, Huaihua, Hunan, 418000, China.
Department of Emergency, First Affiliated Hospital, Hunan University of Medicine, Huaihua, Hunan, 418000, China.
Free Radic Biol Med. 2021 Jan;162:582-591. doi: 10.1016/j.freeradbiomed.2020.11.017. Epub 2020 Nov 26.
Vascular endothelial cell (VEC) inflammation induced by low shear stress plays key roles in the initiation and progression of atherosclerosis (As). Pyroptosis is a form of inflammatory programmed cell death that is critical for As. However, the effect of low shear stress on VEC pyroptosis and the underlying mechanisms were not clear. Here we show that low shear stress promoted VEC pyroptosis and reduced the expression of Ten-Eleven Translocation 2 (TET2) methylcytosine dioxygenase. Loss of TET2 resulted in the upregulation of the expression and activity of mitochondrial respiratory complex II subunit succinate dehydrogenase B (SDHB) by decreasing the recruitment of histone deacetylase 2, independent of DNA demethylation modification. The overexpression of SDHB mediated mitochondrial injury and increased the production of reactive oxygen species (ROS). The administration of ROS scavenger NAC alleviated VEC pyroptosis induced by SDHB overexpression and TET2 shRNA. These findings show that low shear stress induced endothelial cell pyroptosis through the TET2/SDHB/ROS pathway and offer new insights into As.
低切应力诱导的血管内皮细胞(VEC)炎症在动脉粥样硬化(As)的发生和发展中起关键作用。细胞焦亡是一种关键的炎症程序性细胞死亡形式，与 As 密切相关。然而，低切应力对 VEC 细胞焦亡的影响及其潜在机制尚不清楚。在这里，我们发现低切应力促进了 VEC 的细胞焦亡，并降低了 Ten-Eleven Translocation 2 (TET2) 甲基胞嘧啶双加氧酶的表达。TET2 的缺失导致通过减少组蛋白去乙酰化酶 2 的募集，使线粒体呼吸复合物 II 亚基琥珀酸脱氢酶 B (SDHB)的表达和活性上调，而与 DNA 去甲基化修饰无关。SDHB 的过表达介导线粒体损伤并增加活性氧(ROS)的产生。ROS 清除剂 NAC 的给药缓解了由 SDHB 过表达和 TET2 shRNA 引起的 VEC 细胞焦亡。这些发现表明，低切应力通过 TET2/SDHB/ROS 通路诱导内皮细胞焦亡，并为 As 提供了新的见解。
