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Elevating cytosolic NADPH metabolism in endothelial cells ameliorates vascular aging

Author

Listed:
  • Dan Wu

    (Shanghai University
    Tongji University School of Medicine)

  • Bo Tan

    (Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine)

  • Zijie Cheng

    (Shanghai University)

  • Haoqi Li

    (Shanghai University)

  • Huimin Li

    (Tongji University School of Medicine)

  • Yun Yin

    (Tongji University School of Medicine)

  • Fenfen Ma

    (Fudan University)

  • Tao Chen

    (Northwest Institute of Plateau Biology)

  • Xin Dong

    (Shanghai University)

  • Wang Wang

    (University of Washington)

  • Qingxun Hu

    (Shanghai University)

Abstract

Reduced nicotinamide adenine dinucleotide phosphate (NADPH) metabolism is independently regulated in different compartments in endothelial cells (EC). The metabolic profile and functional impact of NADPH during EC senescence remain largely unknown. Using a genetically encoded fluorescent indicator, we find that cytosolic, but not mitochondrial, NADPH level increases during EC senescence. Upregulation of glucose-6-phosphate dehydrogenase (G6PD) further elevates cytosolic NADPH level during EC senescence. Suppression of G6PD S-nitrosylation at C385 potentiates G6PD activity. G6PD overexpression alleviates, while its knockdown aggravates, vascular aging. NADPH is indispensable for G6PD to protect against vascular aging through increasing reduced glutathione and inhibiting HDAC3 activity. Among 1419 FDA-approved drugs, folic acid, catalyzed by methylenetetrahydrofolate dehydrogenase to generate NADPH, effectively alleviates vascular aging in angiotensin II-infused mice and naturally aged mice. The connection between NADPH metabolism and EC senescence provides a unique angle for understanding vascular aging and an efficient target for therapy.

Suggested Citation

  • Dan Wu & Bo Tan & Zijie Cheng & Haoqi Li & Huimin Li & Yun Yin & Fenfen Ma & Tao Chen & Xin Dong & Wang Wang & Qingxun Hu, 2025. "Elevating cytosolic NADPH metabolism in endothelial cells ameliorates vascular aging," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64652-z
    DOI: 10.1038/s41467-025-64652-z
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    References listed on IDEAS

    as
    1. Andrea Annibal & Rebecca George Tharyan & Maribel Fides Schonewolff & Hannah Tam & Christian Latza & Markus Max Karl Auler & Sebastian Grönke & Linda Partridge & Adam Antebi, 2021. "Regulation of the one carbon folate cycle as a shared metabolic signature of longevity," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Andrea Annibal & Rebecca George Tharyan & Maribel Fides Schonewolff & Hannah Tam & Christian Latza & Markus Max Karl Auler & Sebastian Grönke & Linda Partridge & Adam Antebi, 2021. "Author Correction: Regulation of the one carbon folate cycle as a shared metabolic signature of longevity," Nature Communications, Nature, vol. 12(1), pages 1-1, December.
    3. Sandrina Nóbrega-Pereira & Pablo J. Fernandez-Marcos & Thomas Brioche & Mari Carmen Gomez-Cabrera & Andrea Salvador-Pascual & Juana M. Flores & Jose Viña & Manuel Serrano, 2016. "G6PD protects from oxidative damage and improves healthspan in mice," Nature Communications, Nature, vol. 7(1), pages 1-9, April.
    4. Xiongjian Rao & Xiaotao Duan & Weimin Mao & Xuexia Li & Zhonghua Li & Qian Li & Zhiguo Zheng & Haimiao Xu & Min Chen & Peng G. Wang & Yingjie Wang & Binghui Shen & Wen Yi, 2015. "O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth," Nature Communications, Nature, vol. 6(1), pages 1-10, December.
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