内皮细胞HDAC1-ZEB2-NuRD复合体通过调节蛋白S-硫化驱动大动脉动脉瘤和剖析
Shanshan Luo1, Chuiyu Kong1, Shuang Zhao1
1Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School (S.L., C.K., S.Z., Xin Tang, Y.W., X.Z., R.L., X.L., S.S., A.G., L.X., Y.J.), Nanjing Medical University, China.
Circulation
|March 23, 2023
概括
在内皮中减少的蛋白质S-硫化增加了主动脉解剖的风险. ZEB2-HDAC1-NuRD复合体破坏了这一过程,导致疾病. 针对这种途径可以预防大动脉动脉瘤和剖析 (AAD).
科学领域:
- 血管生物学
- 翻译后的修改
- 遗传学
背景情况:
- 大动脉动脉瘤和剖析 (AAD) 是针对内皮的危及生命的血管疾病.
- 蛋白质S-硫化,一种新型的翻译后修饰,在AD病变的作用是不确定的.
- 这项研究研究了内皮蛋白S-硫化对AD调节的作用.
研究的目的:
- 研究蛋白质S-硫化在内皮细胞 (ECs) 调节大动脉瘤和解剖 (AAD) 的作用.
- 识别潜在的分子机制,包括关键的调节基因和涉及AAD的途径.
- 探索基于蛋白质S-硫化调节的AAD的潜在治疗点.
主要方法:
- 在AAD期间检测到EC中的蛋白质S-硫化,并确定了枢纽基因.
- 分析了临床数据并测量了酸酶 (CSE) /硫化 (H2S) 系统水平.
- 产生EC特定的CSE淘汰/过度表达小鼠,并使用蛋白质组学和共免疫沉质谱学.
主要成果:
- 在AAD中观察到内皮蛋白S-硫化降低和CSE/ H2S水平降低.
- 蛋白二硫化异构酶 (PDI) 被确定为关键标,S- 硫化增强其活性并减轻内质网膜应激.
- 发现ZEB2-HDAC1-NuRD复合物抑制了CSE转录,损害了PDI S-硫化,并促进了AAD.
结论:
- 血H2S水平降低与AD风险增加相关.
- 内皮ZEB2-HDAC1-NuRD复合体抑制了CSE,破坏了PDI S-硫化,并推动了AAD的进展.
- 例如通过增加PDI S-硫化或抑制HDAC1来调节这种途径,可以有效地预防AAD的进展.
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