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

• DOI: 10.1161/circulationaha.122.062743
• Publication Date: 2023-03-23T09:00:38Z
• Authors: 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
• Keywords: Endothelial Dysfunction; Haploinsufficiency

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 has not yet been defined. This study aims to investigate whether protein regulates its underlying mechanism.Protein endothelial cells (ECs) during was detected hub genes regulating homeostasis of were identified. Clinical data patients healthy controls collected, level cystathionine γ lyase (CSE)/hydrogen sulfide (H2S) system plasma tissue determined. Mice EC-specific CSE deletion or overexpression generated, progression Unbiased proteomics coimmunoprecipitation combined mass spectrometry analysis conducted determine upstream regulators CSE/H2S findings confirmed transgenic mice.Higher H2S levels associated lower risk AAD, after adjustment common factors. reduced mouse aorta AAD. disulfide isomerase (PDI) main target. PDI at Cys343 Cys400 enhanced activity mitigated endoplasmic reticulum stress. exacerbated, alleviated through PDI. ZEB2 (zinc finger E-box binding homeobox 2) recruited HDAC1-NuRD complex (histone deacetylase 1-nucleosome remodeling deacetylase) repress transcription CTH, gene encoding CSE, inhibited S-sulfhydration. HDAC1 increased Increasing donor GYY4137 pharmacologically inhibiting entinostat AAD.Decreased an dissection. The ZEB2-HDAC1-NuRD transcriptionally represses impairs S-sulfhydration, drives regulation this pathway effectively prevents progression.