SIRT6 deficiency in endothelial cells exacerbates oxidative stress by enhancing HIF1α accumulation and H3K9 acetylation at the Ero1α promoter

作者：Zhenyang Guo, Xueting Yu, Shuang Zhao, Xin Zhong, Dong Huang, Runyang Feng, Peng Li, Zheyan Fang, Yiqing Hu, Zhentao Zhang, Mukaddas Abdurahman, Lei Huang, Yun Zhao, Xiangdong Wang, Junbo Ge, Hua Li · 发表于：Clinical and Translational Medicine · 年份：2023 · DOI：10.1002/ctm2.1377 · 被引用次数：31 · 研究领域：Sirtuins and Resveratrol in Medicine、Endoplasmic Reticulum Stress and Disease、PARP inhibition in cancer therapy

Abstract Background SIRT6, an important NAD + ‐dependent protein, protects endothelial cells from inflammatory and oxidative stress injuries. However, the role of SIRT6 in cardiac microvascular endothelial cells (CMECs) under ischemia‒reperfusion injury (IRI) remains unclear. Methods The HUVECs model of oxygen–glucose deprivation/reperfusion (OGD/R) was established to simulate the endothelial IRI in vitro. Endoplasmic reticulum oxidase 1 alpha (Ero1α) mRNA and protein levels in SIRT6‐overexpressing or SIRT6‐knockdown cells were measured by qPCR and Western blotting. The levels of H 2 O 2 and mitochondrial reactive oxygen species (ROS) were detected to evaluate the status of oxidative stress. The effects of SIRT6 deficiency and Ero1α knockdown on cellular endoplasmic reticulum stress (ERS), inflammation, apoptosis and barrier function were detected by a series of molecular biological experiments and functional experiments in vitro. Chromatin immunoprecipitation, Western blotting, qPCR, and site‐specific mutation experiments were used to examine the underlying molecular mechanisms. Furthermore, endothelial cell‐specific Sirt6 knockout (ecSirt6 −/− ) mice were subjected to cardiac ischemia‒reperfusion surgery to investigate the effects of SIRT6 in CMECs in vivo. Results The expression of Ero1α was significantly upregulated in SIRT6‐knockdown endothelial cells, and high Ero1α expression correlated with the accumulation of H 2 O 2 and mitochondrial ROS. In addition, SIRT6 deficien...