Endothelial HDAC1-ZEB2-NuRD Complex Drives Aortic Aneurysm and Dissection Through Regulation of Protein S-Sulfhydration

作者：Shanshan Luo, Chuiyu Kong, Shuang Zhao, Xin Tang, Yu Wang, Xuechun Zhou, Rui Li, Xingeng Liu, Xinlong Tang, Shixiu Sun, Wei Xie, Zhi‐Ren Zhang, Qing Jing, Aihua Gu, Feng Chen, Dongjin Wang, Hong Wang, Yi Han, Liping Xie, Yong Ji · 发表于：Circulation · 年份：2023 · DOI：10.1161/circulationaha.122.062743 · 被引用次数：88 · 研究领域：Sulfur Compounds in Biology、Advanced Glycation End Products research、Folate and B Vitamins Research

Background: Aortic aneurysm and aortic dissection (AAD) are life-threatening vascular diseases, with endothelium being the primary target for AAD treatment. Protein S-sulfhydration is a newly discovered posttranslational modification whose role in AAD has not yet been defined. This study aims to investigate whether protein S-sulfhydration in the endothelium regulates AAD and its underlying mechanism. Methods: Protein S-sulfhydration in endothelial cells (ECs) during AAD was detected and hub genes regulating homeostasis of the endothelium were identified. Clinical data of patients with AAD and healthy controls were collected, and the level of the cystathionine γ lyase (CSE)/hydrogen sulfide (H 2 S) system in plasma and aortic tissue were determined. Mice with EC-specific CSE deletion or overexpression were generated, and the progression of AAD was determined. Unbiased proteomics and coimmunoprecipitation combined with mass spectrometry analysis were conducted to determine the upstream regulators of the CSE/H 2 S system and the findings were confirmed in transgenic mice. Results: Higher plasma H 2 S levels were associated with a lower risk of AAD, after adjustment for common risk factors. CSE was reduced in the endothelium of AAD mouse and aorta of patients with AAD. Protein S-sulfhydration was reduced in the endothelium during AAD and protein disulfide isomerase (PDI) was the main target. S-sulfhydration of PDI at Cys343 and Cys400 enhanced PDI activity and mitigated endoplasm...