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<p>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.</p><p></p>

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

  • 期刊论文

  • 发表日期：

    2025年1月20日

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  • 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

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 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.