2. Academic Validation
  3. JOSD2 inhibits angiotensin II-induced vascular remodeling by deubiquitinating and stabilizing SMAD7

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

  • Acta Pharmacol Sin. 2025 Jan 20. doi: 10.1038/s41401-024-01437-y.
Si-Rui Shen 1 2,  Zhu-Qi Huang 1 2 3,  Yu-Die Yang 1 2,  Ji-Bo Han 2 4,  Zi-Min Fang 1 2,  Yue Guan 1 2,  Jia-Chen Xu 1 2,  Ju-Lian Min 5,  Yi Wang 2,  Gao-Jun Wu 1,  Zhong-Xiang Xiao 6,  Wu Luo 7 8,  Zhou-Qing Huang 9,  Guang Liang 10 11 12
Affiliations

Affiliations

  • 1 Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
  • 2 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
  • 3 Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China.
  • 4 Department of Cardiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, 314000, China.
  • 5 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 311399, China.
  • 6 Affiliated Yueqing Hospital, Wenzhou Medical University, Yueqing, 325600, China.
  • 7 Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China. wuluo@wmu.edu.cn.
  • 8 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China. wuluo@wmu.edu.cn.
  • 9 Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China. susiehzq@126.com.
  • 10 Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China. wzmcliangguang@163.com.
  • 11 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China. wzmcliangguang@163.com.
  • 12 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 311399, China. wzmcliangguang@163.com.
PMID: 39833306 DOI: 10.1038/s41401-024-01437-y
Abstract

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 TGFβ-SMAD pathway. Furthermore, the LC-MS/MS analysis identified SMAD7, a negative regulator in the TGFβ-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.

Keywords

JOSD2; SMAD7; angiotensin II; ubiquitination; vascular remodeling.

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