温州医科大学梁广等研究人员合作发现，JOSD2通过去泛素化并稳定SMAD7抑制血管紧张素II诱导的血管重构。该研究于2025年1月20日在线发表于国际学术期刊《中国药理学报》。

研究人员鉴定了去泛素化酶Josephin结构域蛋白2（JOSD2）作为一种保护因子，并探讨了其在血管紧张素II（Ang II）诱导的血管重构中的分子机制。首先，研究人员发现JOSD2在Ang II处理的小鼠血管组织的主动脉平滑肌细胞中上调，但在内皮细胞中未见上调。全身敲除JOSD2显著加剧了小鼠Ang II诱导的血管重构。相反，血管平滑肌细胞（VSMC）特异性过表达JOSD2则逆转了Ang II诱导的血管重构。

在体外，JOSD2缺失加剧了Ang II诱导的平滑肌细胞纤维化、增殖和迁移，而这些变化在JOSD2过表达后得到逆转。RNA-seq分析显示，JOSD2在VSMC中的保护作用与TGFβ-SMAD通路相关。此外，LC-MS/MS分析鉴定出TGFβ-SMAD通路中的负调节因子SMAD7是JOSD2的底物。JOSD2特异性结合SMAD7的MH1结构域，通过去除SMAD7上赖氨酸220处的K48连接泛素链，从而维持SMAD7的稳定性。

综上所述，该研究发现JOSD2-SMAD7轴在缓解Ang II诱导的血管重构中至关重要，JOSD2可能是高血压血管重构的新型潜在治疗靶点。

研究人员表示，Ang II水平升高在高血压血管重构的发生中发挥着核心作用。

附：英文原文

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

Author: 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

Issue&Volume: 2025-01-20

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.

DOI: 10.1038/s41401-024-01437-y

Source: https://www.nature.com/articles/s41401-024-01437-y