JOSD2 Inhibits Angiotensin II-induced Vascular Remodeling by Deubiquitinating and Stabilizing SMAD7

Overview

Journal Acta Pharmacol Sin

Date 2025 Jan 20

PMID 39833306

Authors

Si-Rui Shen

Zhu-Qi Huang

Yu-Die Yang

Ji-Bo Han

Zi-Min Fang

Yue Guan

Jia-Chen Xu

Ju-Lian Min

Yi Wang

Gao-Jun Wu

Zhong-Xiang Xiao

Wu Luo

Zhou-Qing Huang

Guang Liang

Affiliations

Soon will be listed here.

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.

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