Shen Si-Rui, Huang Zhu-Qi, Yang Yu-Die, Han Ji-Bo, Fang Zi-Min, Guan Yue, Xu Jia-Chen, Min Ju-Lian, Wang Yi, Wu Gao-Jun, Xiao Zhong-Xiang, Luo Wu, Huang Zhou-Qing, Liang Guang
Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
Acta Pharmacol Sin. 2025 May;46(5):1275-1288. doi: 10.1038/s41401-024-01437-y. Epub 2025 Jan 20.
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.
血管紧张素 II（Ang II）水平升高在高血压血管重塑的发展中起核心作用。在本研究中，我们鉴定去泛素化酶含约瑟芬结构域蛋白 2（JOSD2）为一种保护因子，并研究了其在 Ang II 诱导的血管重塑中的分子机制。首先，我们发现 JOSD2 在 Ang II 刺激的小鼠血管组织的主动脉平滑肌细胞中上调，但在内皮细胞中未上调。JOSD2 的全身敲除显著恶化了 Ang II 诱导的小鼠血管重塑。相反，血管平滑肌细胞（VSMC）特异性 JOSD2 过表达逆转了 Ang II 诱导的血管重塑。在体外，JOSD2 缺陷加剧了 Ang II 诱导的 VSMC 纤维化、增殖和迁移，而这些变化被 JOSD2 过表达逆转。RNA 测序分析表明，JOSD2 在 VSMC 中的保护作用与 TGFβ-SMAD 信号通路有关。此外，液相色谱-串联质谱分析确定 SMAD7 是 TGFβ-SMAD 信号通路中的负调节因子，为 JOSD2 的底物。JOSD2 特异性结合 SMAD7 的 MH1 结构域，在赖氨酸 220 处去除 SMAD7 上与 K48 连接的泛素链，以维持 SMAD7 的稳定性。综上所述，我们的研究结果表明，JOSD2-SMAD7 轴对于缓解 Ang II 诱导的血管重塑至关重要，JOSD2 可能是高血压血管重塑的一个新的潜在治疗靶点。
