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NEXN protects against vascular calcification by promoting SERCA2 SUMOylation and stabilization

Author

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  • Wenjie Guo

    (Southern Medical University
    Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease)

  • Wenjing Guo

    (Southern Medical University
    Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease)

  • Boliang Chen

    (Southern Medical University
    Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease)

  • Zexuan Lin

    (Southern Medical University
    Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease)

  • Zhuohua Wen

    (Southern Medical University)

  • Jiamin Ye

    (Southern Medical University
    Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease)

  • Wei Feng

    (University of California San Diego)

  • Xin Feng

    (Southern Medical University)

  • Jianyun Yan

    (Southern Medical University
    Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease)

  • Pingzhen Yang

    (Southern Medical University
    Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease)

  • Kunfu Ouyang

    (Peking University Shenzhen Hospital)

  • Yifei Li

    (West China Second University Hospital Sichuan University Chengdu)

  • Hanyan Yang

    (Southern Medical University
    Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease)

  • Caiwen Ou

    (Southern Medical University)

  • Canzhao Liu

    (Southern Medical University
    Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease)

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.

Suggested Citation

  • Wenjie Guo & Wenjing Guo & Boliang Chen & Zexuan Lin & Zhuohua Wen & Jiamin Ye & Wei Feng & Xin Feng & Jianyun Yan & Pingzhen Yang & Kunfu Ouyang & Yifei Li & Hanyan Yang & Caiwen Ou & Canzhao Liu, 2025. "NEXN protects against vascular calcification by promoting SERCA2 SUMOylation and stabilization," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63462-7
    DOI: 10.1038/s41467-025-63462-7
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    References listed on IDEAS

    as
    1. Changwon Kho & Ahyoung Lee & Dongtak Jeong & Jae Gyun Oh & Antoine H. Chaanine & Eddy Kizana & Woo Jin Park & Roger J. Hajjar, 2011. "SUMO1-dependent modulation of SERCA2a in heart failure," Nature, Nature, vol. 477(7366), pages 601-605, September.
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