TY - JOUR
T1 - Genetic deletion of CD38 confers post-ischemic myocardial protection through preserved pyridine nucleotides
AU - Boslett, James
AU - Helal, Moustafa
AU - Chini, Eduardo
AU - Zweier, Jay L.
N1 - Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/5
Y1 - 2018/5
N2 - Following the onset of ischemia/reperfusion (I/R), CD38 activation occurs and is associated with depletion of NAD(P)(H) in the heart as well as myocardial injury and endothelial dysfunction. Studies with pharmacological inhibitors suggest that the NADP+-hydrolyzing ability of CD38 can deplete the NAD(P)(H) pools. However, there is a need for more specific studies on the importance of CD38 and its role in the process of endothelial dysfunction and myocardial injury in the post-ischemic heart. Therefore, experiments were performed in hearts of mice with global gene knockout of CD38. Isolated perfused CD38−/− and wild type (WT) mouse hearts were studied to determine the link between CD38 activation, the levels of NADP(H), endothelial dysfunction, and myocardial injury after I/R. Genetic deletion of CD38 preserves the myocardial and endothelial NADP(H) pools compared to WT. Whole heart BH4 levels in CD38−/− hearts were also preserved. Post-ischemic levels of cGMP were greatly depleted in WT hearts, but preserved to near baseline levels in CD38−/− hearts. The preservation of these metabolite pools in CD38−/− hearts was accompanied by near full recovery of NOS-dependent coronary flow, while in WT hearts, severe impairment of endothelial function and NOS uncoupling occurred with decreased NO and enhanced superoxide generation. CD38−/− hearts also exhibited marked protection against I/R with preserved glutathione levels, increased recovery of left ventricular contractile function, decreased myocyte enzyme release, and decreased infarct size. Thus, CD38 activation causes post-ischemic depletion of NADP(H) within the heart, with severe depletion from the endothelium, resulting in endothelial dysfunction and myocardial injury.
AB - Following the onset of ischemia/reperfusion (I/R), CD38 activation occurs and is associated with depletion of NAD(P)(H) in the heart as well as myocardial injury and endothelial dysfunction. Studies with pharmacological inhibitors suggest that the NADP+-hydrolyzing ability of CD38 can deplete the NAD(P)(H) pools. However, there is a need for more specific studies on the importance of CD38 and its role in the process of endothelial dysfunction and myocardial injury in the post-ischemic heart. Therefore, experiments were performed in hearts of mice with global gene knockout of CD38. Isolated perfused CD38−/− and wild type (WT) mouse hearts were studied to determine the link between CD38 activation, the levels of NADP(H), endothelial dysfunction, and myocardial injury after I/R. Genetic deletion of CD38 preserves the myocardial and endothelial NADP(H) pools compared to WT. Whole heart BH4 levels in CD38−/− hearts were also preserved. Post-ischemic levels of cGMP were greatly depleted in WT hearts, but preserved to near baseline levels in CD38−/− hearts. The preservation of these metabolite pools in CD38−/− hearts was accompanied by near full recovery of NOS-dependent coronary flow, while in WT hearts, severe impairment of endothelial function and NOS uncoupling occurred with decreased NO and enhanced superoxide generation. CD38−/− hearts also exhibited marked protection against I/R with preserved glutathione levels, increased recovery of left ventricular contractile function, decreased myocyte enzyme release, and decreased infarct size. Thus, CD38 activation causes post-ischemic depletion of NADP(H) within the heart, with severe depletion from the endothelium, resulting in endothelial dysfunction and myocardial injury.
KW - Coronary circulation
KW - Endothelium
KW - Ischemia
KW - Nitric oxide
KW - Oxidant stress
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U2 - 10.1016/j.yjmcc.2018.02.015
DO - 10.1016/j.yjmcc.2018.02.015
M3 - Article
C2 - 29476764
AN - SCOPUS:85044438481
SN - 0022-2828
VL - 118
SP - 81
EP - 94
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -