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N6-methylation of RNA-bound adenosine regulator HNRNPC promotes vascular endothelial dysfunction in type 2 diabetes mellitus by activating the PSEN1-mediated Notch pathway

  • Ying Cai
    Affiliations
    Department of Rehabilitation Medicine, Xiangya Hospital Central South University, Changsha 410008, P. R. China

    National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha 410008, P. R. China
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  • Tao Chen
    Affiliations
    The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, P. R. China
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  • Mingzhu Wang
    Affiliations
    Department of Rehabilitation Medicine, Xiangya Hospital Central South University, Changsha 410008, P. R. China

    National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha 410008, P. R. China
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  • Lihua Deng
    Affiliations
    Department of Rehabilitation Medicine, Xiangya Hospital Central South University, Changsha 410008, P. R. China

    National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha 410008, P. R. China
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  • Cui Li
    Affiliations
    Department of Rehabilitation Medicine, Xiangya Hospital Central South University, Changsha 410008, P. R. China

    National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha 410008, P. R. China
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  • Siqian Fu
    Affiliations
    Department of Rehabilitation Medicine, Xiangya Hospital Central South University, Changsha 410008, P. R. China

    National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha 410008, P. R. China
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  • Kangling Xie
    Correspondence
    Corresponding author at: Department of Rehabilitation Medicine, Xiangya Hospital Central South University, No.87, Xiangya Road, Kaifu District, Changsha 410008, Hunan Province, P. R. China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha 410008, Hunan Province, P. R. China
    Affiliations
    Department of Rehabilitation Medicine, Xiangya Hospital Central South University, Changsha 410008, P. R. China

    National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha 410008, P. R. China
    Search for articles by this author
Published:January 18, 2023DOI:https://doi.org/10.1016/j.diabres.2023.110261

      Abstract

      Aim

      The regulatory mechanism of m6A regulators in vascular endothelial function of type 2 diabetes mellitus (T2DM) remains largely unknown. We addressed this issue based on the data retrieved Gene Expression Omnibus (GEO) database and experimental validations.

      Methods

      Expression of m6A methylation regulators was evaluated in T2DM samples of GSE76894 dataset and GSE156341 dataset. Further analysis of candidate m6A methylation regulators was conducted in the thoracic aorta of db/db mice and high glucose (HG)-induced human umbilical vein endothelial cells (HUVECs). Ectopic expression and depletion experiments were conducted to detect effects of m6A methylation regulators on vascular endothelial function in T2DM.

      Results

      It emerged that three m6A methylation regulators (HNRNPC, RBM15B, and ZC3H13) were highly expressed in T2DM, which were related to vascular EC function, showing diagnostic values for T2DM. HNRNPC expression in the thoracic aorta of db/db mice was higher than that in heterozygous db mice, and HNRNPC expression in HG-induced HUVECs was upregulated when compared with normal glucose-exposed HUVECs. Furthermore, HNRNPC activated PSEN1-dependent Notch pathway to induce eNOS inactivation and NO production decrease, thereby causing vascular endothelial dysfunction in T2DM.

      Conclusions

      HNRNPC impaired vascular endothelial function to enhance the development of vascular complications in T2DM through PSEN1-mediated Notch signaling pathway.

      Keywords

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