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

医学 蛋白质二硫键异构酶 胱硫醚β合酶 内皮 内质网 内皮功能障碍 单倍率不足 内科学 内分泌学 细胞生物学 生物化学 生物 基因 半胱氨酸 表型
作者
Shanshan Luo,Chuiyu Kong,Shuang Zhao,Xin Tang,Yu Wang,Xuechun Zhou,Rui Li,Liu Xin-geng,Xingming Tang,Shixiu Sun,Wei Xie,Zhi‐Ren Zhang,Qing Jing,Aihua Gu,Feng Chen,Dongjin Wang,Hong Wang,Yi Han,Liping Xie,Yong Ji
出处
期刊:Circulation [Ovid Technologies (Wolters Kluwer)]
卷期号:147 (18): 1382-1403 被引量:23
标识
DOI:10.1161/circulationaha.122.062743
摘要

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.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 (H2S) 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/H2S system and the findings were confirmed in transgenic mice.Higher plasma H2S 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 endoplasmic reticulum stress. EC-specific CSE deletion was exacerbated, and EC-specific overexpression of CSE alleviated the progression of AAD through regulating the S-sulfhydration of PDI. ZEB2 (zinc finger E-box binding homeobox 2) recruited the HDAC1-NuRD complex (histone deacetylase 1-nucleosome remodeling and deacetylase) to repress the transcription of CTH, the gene encoding CSE, and inhibited PDI S-sulfhydration. EC-specific HDAC1 deletion increased PDI S-sulfhydration and alleviated AAD. Increasing PDI S-sulfhydration with the H2S donor GYY4137 or pharmacologically inhibiting HDAC1 activity with entinostat alleviated the progression of AAD.Decreased plasma H2S levels are associated with an increased risk of aortic dissection. The endothelial ZEB2-HDAC1-NuRD complex transcriptionally represses CTH, impairs PDI S-sulfhydration, and drives AAD. The regulation of this pathway effectively prevents AAD progression.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
为你博弈完成签到,获得积分10
刚刚
852发布了新的文献求助10
1秒前
小鱼发布了新的文献求助10
1秒前
2秒前
2秒前
3秒前
4秒前
2113完成签到,获得积分10
4秒前
5秒前
上官冷不冷完成签到,获得积分10
5秒前
mhy发布了新的文献求助10
6秒前
嗯哼应助专一的白萱采纳,获得20
6秒前
6秒前
瘦瘦发布了新的文献求助10
6秒前
大秦完成签到,获得积分20
7秒前
1257应助太阳花采纳,获得10
7秒前
孙鑫发布了新的文献求助10
9秒前
徐徐图之完成签到 ,获得积分10
10秒前
没所谓完成签到,获得积分10
11秒前
hhhhhhhhhh完成签到 ,获得积分10
11秒前
11秒前
GY发布了新的文献求助10
11秒前
sunnypartly完成签到,获得积分10
11秒前
甜甜灵槐发布了新的文献求助10
12秒前
12秒前
吴1完成签到,获得积分10
14秒前
orixero应助可青采纳,获得10
14秒前
科研通AI2S应助知名不具采纳,获得10
15秒前
yuan发布了新的文献求助10
16秒前
Vvvnnnaa1完成签到,获得积分10
16秒前
晚灯君完成签到 ,获得积分10
16秒前
上官若男应助顺利可兰采纳,获得10
16秒前
wangion完成签到,获得积分10
16秒前
科研通AI2S应助云淡风轻采纳,获得10
17秒前
汉堡包应助椰子糖采纳,获得10
17秒前
17秒前
希望天下0贩的0应助China采纳,获得10
19秒前
无限的水壶完成签到 ,获得积分10
19秒前
wangxc完成签到 ,获得积分10
20秒前
高分求助中
Sustainability in Tides Chemistry 1500
TM 5-855-1(Fundamentals of protective design for conventional weapons) 1000
Gerard de Lairesse : an artist between stage and studio 500
Digging and Dealing in Eighteenth-Century Rome 500
Queer Politics in Times of New Authoritarianisms: Popular Culture in South Asia 500
Livre et militantisme : La Cité éditeur 1958-1967 500
Retention of title in secured transactions law from a creditor's perspective: A comparative analysis of selected (non-)functional approaches 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3061124
求助须知:如何正确求助?哪些是违规求助? 2716510
关于积分的说明 7450143
捐赠科研通 2362455
什么是DOI,文献DOI怎么找? 1252166
科研通“疑难数据库(出版商)”最低求助积分说明 607939
版权声明 596536