ArticleProceedings of the National Academy of Sciences of the United States of America2015
Depletion of NADP(H) due to CD38 activation triggers endothelial dysfunction in the postischemic heart.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 64 citations in OpenAlex.
- Molecular Mechanisms Governing Vascular Function in Heart Failure.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- Perioperative immune dynamics during cardiopulmonary bypass and association with major adverse postoperative events.Frontiers in cardiovascular medicine · 2026Article
- Endothelial cell metabolism in cardiovascular physiology and disease.Nature reviews. Cardiology · 2025Review
- CD38 connects the heart and brain.Translational psychiatry · 2025Review
- Review
- NADPCurrent medicinal chemistry · 2025Review
- Comprehensive bioinformatics analysis of hub genes in ischemic heart failure and atrial fibrillation.Frontiers in cardiovascular medicine · 2025Article
- Promotion of nitric oxide production: mechanisms, strategies, and possibilities.Frontiers in physiology · 2025Review
- NAD+ metabolism and therapeutic strategies in cardiovascular diseases.Atherosclerosis plus · 2024Review
- Hacking the Lipidome: New Ferroptosis Strategies in Cancer Therapy.Biomedicines · 2024Review
- Protein lysine acetylation does not contribute to the high rates of fatty acid oxidation seen in the post-ischemic heart.Scientific reports · 2024Article
- NAD metabolism: Role in senescence regulation and aging.Aging cell · 2024Review
- The role of CD38 in ischemia reperfusion injury in cardiopulmonary bypass and thoracic transplantation: a narrative review.Journal of thoracic disease · 2023Review
- Novel Therapeutic Strategies in the Treatment of Systemic Sclerosis.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Effects of Apocynin, a NADPH Oxidase Inhibitor, in the Protection of the Heart from Ischemia/Reperfusion Injury.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Review
- Reduced nicotinamide adenine dinucleotide phosphate in redox balance and diseases: a friend or foe?Acta pharmacologica Sinica · 2022Review
- Mechanisms and clinical implications of endothelium-dependent vasomotor dysfunction in coronary microvasculature.American journal of physiology. Heart and circulatory physiology · 2022Review
- NADJournal of lipid and atherosclerosis · 2022Review
- Benefits in cardiac function by CD38 suppression: Improvement in NADJournal of molecular and cellular cardiology · 2022Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
In the postischemic heart, coronary vasodilation is impaired due to loss of endothelial nitric oxide synthase (eNOS) function. Although the eNOS cofactor tetrahydrobiopterin (BH4) is depleted, its repletion only partially restores eNOS-mediated coronary vasodilation, indicating that other critical factors trigger endothelial dysfunction. Therefore, studies were performed to characterize the unidentified factor(s) that trigger endothelial dysfunction in the postischemic heart. We observed that depletion of the eNOS substrate NADPH occurs in the postischemic heart with near total depletion from the endothelium, triggering impaired eNOS function and limiting BH4 rescue through NADPH-dependent salvage pathways. In isolated rat hearts subjected to 30 min of ischemia and reperfusion (I/R), depletion of the NADP(H) pool occurred and was most marked in the endothelium, with >85% depletion. Repletion of NADPH after I/R increased NOS-dependent coronary flow well above that with BH4 alone. With combined NADPH and BH4 repletion, full restoration of NOS-dependent coronary flow occurred. Profound endothelial NADPH depletion was identified to be due to marked activation of the NAD(P)ase-activity of CD38 and could be prevented by inhibition or specific knockdown of this protein. Depletion of the NADPH precursor, NADP(+), coincided with formation of 2'-phospho-ADP ribose, a CD38-derived signaling molecule. Inhibition of CD38 prevented NADP(H) depletion and preserved endothelium-dependent relaxation and NO generation with increased recovery of contractile function and decreased infarction in the postischemic heart. Thus, CD38 activation is an important cause of postischemic endothelial dysfunction and presents a novel therapeutic target for prevention of this dysfunction in unstable coronary syndromes.
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