Abstract 19525: Knockout of CD38 Preserves Endothelial Function in the Postischemic Heart through Reduced Nicotinamide Adenine Dinucleotide Phosphate Salvage

Abstract

Introduction: Cardiac ischemia/reperfusion (I/R) injury causes dysfunction in the coronary endothelium, resulting in loss of vascular relaxation and decreased tissue perfusion. Prior data with pharmacological inhibitors suggests that CD38 plays a role in I/R-induced vascular endothelial dysfunction (VED) through consumption of NADPH precursor NADP, limiting the supply of NADPH for nitric oxide (NO) production from endothelial NO synthase (eNOS) and decreasing NOS-dependent coronary flow (NDCF). In order to definitively determine the role of CD38 in cardiac I/R injury and endothelial dysfunction, we performed studies on hearts of wild type (WT) and CD38 -/- mice. Methods: Isolated Langendorff perfused hearts of WT (n=9) and CD38 -/- mice (n=7) were subjected to 30 min ischemia (I) and contractile function and coronary flow were monitored through 30 min reperfusion (R) with an intraventricular balloon and Doppler flow probe, respectively. At 30 min R, NDCF was measured with administration of NOS inhibitor L-NAME and then hearts were frozen for high performance liquid chromatography (HPLC) measurements of NADP(H) and NAD(H). Results: There was no difference in contractile function recovery between groups. However, hearts from CD38 -/- mice had enhanced recovery of both NADP(H) and NAD(H) (47.4 +/- 3.2 and 42.2 +/- 3.3% higher). Furthermore, at 30 min R, hearts from CD38 -/- mice had much higher post-ischemic recovery of coronary flow (14.64 +/- 3.50% higher) and NDCF (48.7 +/- 5.5% higher) compared to WT mice (Fig 1 & 2). Conclusion: Thus, we observe that CD38 activation is a key mechanism contributing to NADP(H) depletion and VED in the postischemic heart.