NEXN protects against vascular calcification by promoting SERCA2 SUMOylation and stabilization
Wenjie Guo, Wenjing Guo, Boliang Chen, Zexuan Lin, Zhuohua Wen, Jianping Ye, Wei Feng, Xin Feng, Jianyun Yan, Pingzhen Yang, Kunfu Ouyang, Yifei Li, Hanyan Yang, Caiwen Ou, Canzhao Liu
Abstract
Vascular calcification, a key risk factor for cardiovascular diseases, is driven by the phenotypic transition of vascular smooth muscle cells from a contractile to an osteogenic phenotype. NEXN, a protein highly associated with heart function, has also been implicated as a potential susceptibility factor in the development of coronary artery disease, but its role in the progression of vascular calcification remains unclear. In this study, multi-transcriptomics analysis and various animal models of male mice were used to explore the cell-specific roles and molecular mechanisms of NEXN in vascular calcification. Here, we show that vascular smooth muscle cell-specific NEXN knockout exacerbates calcification, while NEXN overexpression alleviates it. Mechanistically, NEXN interacts with SERCA2, enhancing its SUMOylation, stability, and function, thereby protecting against calcification. These findings suggest potential therapeutic strategies by targeting NEXN-SERCA2 interactions or enhancing SERCA2 SUMOylation to prevent vascular calcification and its complications. Vascular calcification, a key risk factor of cardiovascular diseases, involves smooth muscle cells shifting to osteogenic phenotype. Here, the authors show that NEXN inhibits this process and protects against calcification by stabilizing SERCA2.