JOSD2 inhibits angiotensin II-induced vascular remodeling by deubiquitinating and stabilizing SMAD7

被引:0
作者
Shen, Si-rui [1 ,2 ]
Huang, Zhu-qi [1 ,2 ,3 ,4 ]
Yang, Yu-die [1 ,2 ]
Han, Ji-bo [2 ,5 ]
Fang, Zi-min [1 ,2 ]
Guan, Yue [1 ,2 ]
Xu, Jia-chen [1 ,2 ]
Min, Ju-lian [6 ]
Wang, Yi [2 ]
Wu, Gao-jun [1 ]
Xiao, Zhong-xiang [7 ]
Luo, Wu [1 ,2 ]
Huang, Zhou-qing [1 ]
Liang, Guang [1 ,2 ,6 ]
机构
[1] Wenzhou Med Univ, Affiliated Hosp 1, Dept Cardiol, Wenzhou 325035, Peoples R China
[2] Wenzhou Med Univ, Chem Biol Res Ctr, Sch Pharmaceut Sci, Wenzhou 325035, Peoples R China
[3] Zhejiang Prov Peoples Hosp, Hangzhou Med Coll, Affiliated Peoples Hosp, Dept Pharm, Hangzhou 310014, Peoples R China
[4] Zhejiang Prov Peoples Hosp, Affiliated Peoples Hosp, Inst Inflammat, Hangzhou Med Coll, Hangzhou 310014, Peoples R China
[5] Jiaxing Univ, Affiliated Hosp 2, Dept Cardiol, Jiaxing 314000, Peoples R China
[6] Hangzhou Med Coll, Sch Pharmaceut Sci, Hangzhou 311399, Peoples R China
[7] Wenzhou Med Univ, Affiliated Yueqing Hosp, Yueqing 325600, Peoples R China
来源
ACTA PHARMACOLOGICA SINICA | 2025年
基金
中国国家自然科学基金;
关键词
JOSD2; vascular remodeling; SMAD7; angiotensin II; ubiquitination; SMOOTH-MUSCLE-CELLS; UBIQUITIN; DEGRADATION; ENZYMES;
D O I
10.1038/s41401-024-01437-y
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Increased level of angiotensin II (Ang II) plays a central role in the development of hypertensive vascular remodeling. In this study, we identified the deubiquitinating enzyme Josephin domain-containing protein 2 (JOSD2) as a protective factor and investigated its molecular mechanism in Ang II-induced vascular remodeling. First, we found that JOSD2 was upregulated in aortic smooth muscle cells, but not in endothelial cells of Ang II-challenged mouse vascular tissues. Whole-body knockout of JOSD2 significantly deteriorated Ang II-induced vascular remodeling in mice. Conversely, Ang II-induced vascular remodeling was reversed by vascular smooth muscle cell (VSMC)-specific JOSD2 overexpression. In vitro, JOSD2 deficiency aggravated Ang II-induced fibrosis, proliferation, and migration VSMCs, while these changes were reversed by JOSD2 overexpression. RNA-seq analysis showed that the protective effects of JOSD2 in VSMCs were related to the TGF beta-SMAD pathway. Furthermore, the LC-MS/MS analysis identified SMAD7, a negative regulator in the TGF beta-SMAD pathway, as the substrate of JOSD2. JOSD2 specifically bound to the MH1 domain of SMAD7 to remove the K48-linked ubiquitin chains from SMAD7 at lysine 220 to sustain SMAD7 stability. Taken together, our finding reveals that the JOSD2-SMAD7 axis is critical for relieving Ang II-induced vascular remodeling and JOSD2 may be a novel and potential therapeutic target for hypertensive vascular remodeling.
引用
收藏
页码:1275 / 1288
页数:14
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