title: Depletion of NADP(H) due to CD38 activation triggers endothelial dysfunction in the postischemic heart.
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.
authors: Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University Medical Center, Columbus, OH 43210;
authors: Levy A
authors: LA
authors: Reyes
authors: Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University Medical Center, Columbus, OH 43210;
authors: James
authors: J
authors: Boslett
authors: Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University Medical Center, Columbus, OH 43210;
authors: Saradhadevi
authors: S
authors: Varadharaj
authors: Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University Medical Center, Columbus, OH 43210;
authors: Francesco
authors: F
authors: De Pascali
authors: Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University Medical Center, Columbus, OH 43210;
authors: Craig
authors: C
authors: Hemann
authors: Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University Medical Center, Columbus, OH 43210;
authors: Lawrence J
authors: LJ
authors: Druhan
authors: Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University Medical Center, Columbus, OH 43210; Division of Cardiology, University of Perugia School of Medicine, 06156 Perugia, Italy.
authors: Giuseppe
authors: G
authors: Ambrosio
authors: Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University Medical Center, Columbus, OH 43210;
authors: Mohamed
authors: M
authors: El-Mahdy
authors: Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University Medical Center, Columbus, OH 43210; Jay.Zweier@osumc.edu.
authors: Jay L
authors: JL
authors: Zweier
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000737:chemistry; D003324:Coronary Artery Disease / Q000473:pathology; D004578:Electron Spin Resonance Spectroscopy; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D006321:Heart / Q000502:physiology; D000860:Hypoxia / Q000473:pathology; D007511:Ischemia / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009249:NADP / Q000378:metabolism*; D009569:Nitric Oxide / Q000737:chemistry; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury
chemical_list: D034741:RNA, Small Interfering; D001708:Biopterins; D009569:Nitric Oxide; D009249:NADP; D052250:Nitric Oxide Synthase Type III; D051997:ADP-ribosyl Cyclase 1; C003402:sapropterin
keywords: endothelial dysfunction; endothelial nitric oxide synthase; ischemia reperfusion injury; nitric oxide; tetrahydrobiopterin