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
Jessie完成签到 ,获得积分10
1秒前
1秒前
小二郎应助hsy采纳,获得10
1秒前
怡然依柔发布了新的文献求助30
2秒前
Star1983发布了新的文献求助10
3秒前
mingkle完成签到,获得积分10
3秒前
拥抱爱莉发布了新的文献求助10
3秒前
Micheal完成签到,获得积分10
4秒前
牛马完成签到,获得积分10
4秒前
4秒前
Hello应助云_123采纳,获得10
5秒前
An慧完成签到,获得积分10
5秒前
hutu发布了新的文献求助10
5秒前
6秒前
6秒前
6秒前
7秒前
wanci应助鲁滨逊采纳,获得10
7秒前
北极星162完成签到,获得积分10
7秒前
8秒前
yuzhanli完成签到,获得积分10
8秒前
原来我是狼人完成签到,获得积分20
8秒前
lh完成签到 ,获得积分10
9秒前
果然如此完成签到,获得积分10
10秒前
张佳佳发布了新的文献求助10
10秒前
haifenghou发布了新的文献求助10
10秒前
11秒前
12秒前
12秒前
哭泣雅绿发布了新的文献求助10
12秒前
余海川发布了新的文献求助30
13秒前
积极新烟发布了新的文献求助10
13秒前
WG完成签到,获得积分10
13秒前
优秀的盼夏完成签到,获得积分10
13秒前
rhei发布了新的文献求助10
14秒前
rgaerva应助mmyhn采纳,获得10
15秒前
hutu完成签到,获得积分20
15秒前
wlei9534完成签到,获得积分10
16秒前
hyaoooo发布了新的文献求助10
16秒前
怡然依柔完成签到,获得积分10
16秒前
高分求助中
Sustainability in Tides Chemistry 2800
The Young builders of New china : the visit of the delegation of the WFDY to the Chinese People's Republic 1000
Rechtsphilosophie 1000
Bayesian Models of Cognition:Reverse Engineering the Mind 888
Le dégorgement réflexe des Acridiens 800
Defense against predation 800
Very-high-order BVD Schemes Using β-variable THINC Method 568
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 3135577
求助须知:如何正确求助?哪些是违规求助? 2786454
关于积分的说明 7777484
捐赠科研通 2442441
什么是DOI,文献DOI怎么找? 1298558
科研通“疑难数据库(出版商)”最低求助积分说明 625193
版权声明 600847