title: Luteolinidin Protects the Postischemic Heart through CD38 Inhibition with Preservation of NAD(P)(H).
abstract: We recently showed that ischemia/reperfusion (I/R) of the heart causes CD38 activation with resultant depletion of the cardiac NADP(H) pool, which is most marked in the endothelium. This NADP(H) depletion was shown to limit the production of nitric oxide by endothelial nitric oxide synthase (eNOS), which requires NADPH for nitric oxide production, resulting in greatly altered endothelial function. Therefore, intervention with CD38 inhibitors could reverse postischemic eNOS-mediated endothelial dysfunction. Here, we evaluated the potency of the CD38 inhibitor luteolinidin, an anthocyanidin, at blocking CD38 activity and preserving endothelial and myocardial function in the postischemic heart. Initially, we characterized luteolinidin as a CD38 inhibitor in vitro to determine its potency and mechanism of inhibition. We then tested luteolinidin in the ex vivo isolated heart model, where we determined luteolinidin uptake with aqueous and liposomal delivery methods. Optimal delivery methods were then further tested to determine the effect of luteolinidin on postischemic NAD(P)(H) and tetrahydrobiopterin levels. Finally, through nitric oxide synthase-dependent coronary flow and left ventricular functional measurements, we evaluated the efficacy of luteolinidin to protect vascular and contractile function, respectively, after I/R. With enhanced postischemic preservation of NADPH and tetrahydrobiopterin, there was a dose-dependent effect of luteolinidin on increasing recovery of endothelium-dependent vasodilatory function, as well as enhancing the recovery of left ventricular contractile function with increased myocardial salvage. Thus, luteolinidin is a potent CD38 inhibitor that protects the heart against I/R injury with preservation of eNOS function and prevention of endothelial dysfunction.
authors.affiliation: Department of Internal Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio (J.B., C.H., J.L.Z.); and Laboratory of Cytophysiology, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China (Y.J.Z., H.-C.L.).
authors.forename: James
authors.initials: J
authors.lastname: Boslett
authors.affiliation: Department of Internal Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio (J.B., C.H., J.L.Z.); and Laboratory of Cytophysiology, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China (Y.J.Z., H.-C.L.).
authors.forename: Craig
authors.initials: C
authors.lastname: Hemann
authors.affiliation: Department of Internal Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio (J.B., C.H., J.L.Z.); and Laboratory of Cytophysiology, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China (Y.J.Z., H.-C.L.).
authors.forename: Yong Juan
authors.initials: YJ
authors.lastname: Zhao
authors.affiliation: Department of Internal Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio (J.B., C.H., J.L.Z.); and Laboratory of Cytophysiology, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China (Y.J.Z., H.-C.L.).
authors.forename: Hon-Cheung
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio (J.B., C.H., J.L.Z.); and Laboratory of Cytophysiology, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China (Y.J.Z., H.-C.L.) jay.zweier@osumc.edu.
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D000872:Anthocyanins / Q000494:pharmacology / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism*; D009249:NADP / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D000872:Anthocyanins; D002316:Cardiotonic Agents; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D009249:NADP; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; C518537:luteolinidin