Elevating cytosolic NADPH metabolism in endothelial cells ameliorates vascular aging
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.
Authors
- Zijie Cheng (ORCID: https://orcid.org/0000-0002-5341-0818)
- Xin Wen Dong (ORCID: https://orcid.org/0000-0003-3709-0655)
- Fenfen Ma
- Bo Tan (ORCID: https://orcid.org/0000-0002-9855-1470)
- Haoqi Li (ORCID: https://orcid.org/0000-0002-9943-329X)
- Yun Yin (ORCID: https://orcid.org/0000-0002-4143-0256)
- Tao Chen (ORCID: https://orcid.org/0000-0002-8016-9732)
- Dan Wu (ORCID: https://orcid.org/0000-0002-8732-5988)
- Wang Wang (ORCID: https://orcid.org/0000-0001-9093-412X)
- Qingxun Hu (ORCID: https://orcid.org/0000-0001-9288-6491)
- Huimin Li
Institutions
- Shanghai University (CN)
- Qinghai University (CN)
- Tongji University (CN)
- Shanghai University of Engineering Science (CN)
- Shanghai University of Traditional Chinese Medicine (CN)
- Xinjiang Institute of Ecology and Geography (CN)
- Pudong Medical Center (CN)
- Shuguang Hospital (CN)
- Tongji Hospital (CN)
- MRC Mitochondrial Biology Unit (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-03
- DOI
- https://doi.org/10.1038/s41467-025-64652-z
- Citations
- 1
- Primary Topic
- Nitric Oxide and Endothelin Effects
- Type
- article
- Field-Weighted Citation Impact
- 1.16
Funders
- American Heart Association
- Shanghai Municipal Health Commission
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Science and Technology Commission of Shanghai Municipality
- Youth Innovation Promotion Association of the Chinese Academy of Sciences
- Youth Innovation Promotion Association