Guo Wenjie, Guo Wenjing, Chen Boliang, Lin Zexuan, Wen Zhuohua, Ye Jiamin, Feng Wei, Feng Xin, Yan Jianyun, Yang Pingzhen, Ouyang Kunfu, Li Yifei, Yang Hanyan, Ou Caiwen, Liu Canzhao
Department of Cardiology, Laboratory of Heart Center, Heart Center, Center for Translational Medicine Research, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, China.
Nat Commun. 2025 Aug 29;16(1):8074. doi: 10.1038/s41467-025-63462-7.
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.
血管钙化是心血管疾病的关键危险因素，它由血管平滑肌细胞从收缩表型向成骨表型的转变所驱动。NEXN是一种与心脏功能高度相关的蛋白质，也被认为是冠状动脉疾病发展中的潜在易感因素，但其在血管钙化进展中的作用仍不清楚。在本研究中，利用多转录组学分析和雄性小鼠的各种动物模型，探讨NEXN在血管钙化中的细胞特异性作用和分子机制。在此，我们表明血管平滑肌细胞特异性敲除NEXN会加剧钙化，而NEXN过表达则会减轻钙化。从机制上讲，NEXN与SERCA2相互作用，增强其SUMO化、稳定性和功能，从而预防钙化。这些发现提示了通过靶向NEXN-SERCA2相互作用或增强SERCA2 SUMO化来预防血管钙化及其并发症的潜在治疗策略。
