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.