NEXN protects against vascular calcification by promoting SERCA2 SUMOylation and stabilization
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.
Authors
- Zhi‐Hong Wen (ORCID: https://orcid.org/0000-0003-4411-044X)
- Wenjie Guo (ORCID: https://orcid.org/0000-0001-8506-3905)
- Wei Feng (ORCID: https://orcid.org/0009-0001-0173-874X)
- Jianyun Yan (ORCID: https://orcid.org/0000-0002-6962-1169)
- Caiwen Ou (ORCID: https://orcid.org/0000-0002-9515-6125)
- Jianping Ye (ORCID: https://orcid.org/0000-0003-3875-365X)
- Kunfu Ouyang (ORCID: https://orcid.org/0000-0003-0292-375X)
- Canzhao Liu (ORCID: https://orcid.org/0000-0002-9035-5723)
- Boliang Chen
- Wenjing Guo (ORCID: https://orcid.org/0000-0001-8271-9374)
- Pingzhen Yang (ORCID: https://orcid.org/0000-0003-3751-8463)
- Yifei Li (ORCID: https://orcid.org/0000-0002-3096-4287)
- Zhiming Lin
- Xin Feng (ORCID: https://orcid.org/0000-0002-4703-5409)
- Hanyan Yang (ORCID: https://orcid.org/0009-0003-4830-795X)
Institutions
- Sichuan University (CN)
- University of California San Diego (US)
- West China Second University Hospital of Sichuan University (CN)
- Key Laboratory of Guangdong Province (CN)
- Zhujiang Hospital (CN)
- Dongguan People’s Hospital (CN)
- Peking University Shenzhen Hospital (CN)
- Guangdong Provincial Center for Disease Control and Prevention (CN)
- Southern Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1038/s41467-025-63462-7
- Citations
- 3
- Primary Topic
- Protein Tyrosine Phosphatases
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- National Natural Science Foundation of China
- University of California, San Diego
- Basic and Applied Basic Research Foundation of Guangdong Province