Abstract 17454: ADP Ribosyl Cyclase (CD38) Degrades the NADP(H) Pool Causing Endothelial Nitric Oxide Synthase Dysfunction in the Postischemic Heart
In postischemic myocardium impaired endothelial function occurs with endothelial nitric oxide synthase (eNOS) dysfunction and this limits vasodilation and tissue perfusion. Recently, we have shown in the isolated rat heart, that during ischemia/reperfusion (I/R) injury both tetrahydrobiopterin (BH4) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) are depleted, and when these lost eNOS cofactors/substrates are repleted the activity of the dysfunctional enzyme is largely restored and vasodilation markedly improved. In addition to its role as an obligatory NOS substrate, NADPH is also required for maintenance of BH4 levels through dihydrofolate reductase. We observe that endothelial NADP(H) levels are >80% depleted in reperfused hearts following 30 min of global ischemia and NADPH repletion yields a marked 30% increase in coronary flow. However, while NADPH repletion is highly beneficial, the pathway of its degradation was unknown. We show that following 30 min I and R, the oxidized form of NADPH, NADP+, falls in the whole heart tissue to 29% ± 1% of pre-ischemic levels and to less than 10% in the endothelium, which limits its availability to replenish NADPH in turn hindering vasodilation. We further show that the fall of NADP+ coincides with the production of nicotinamide and 2-phospho-cyclic adenosine diphosphoribose (2-P-cADPR), a signaling molecule with the potential to liberate Ca2+ via IP3 pathway. These data suggest that the enzyme ADP Ribosyl Cyclase (CD38) is activated and depletes NADP+. Treatment with the CD38 inhibitor -NAD+ enhanced the recovery of postischemic coronary flow. CD38 is known to be activated by oxidative stress. Thus, we observe that CD38 is activated in the postischemic heart and degrades the NADP(H) pool with production of cADPR which can induce release of Ca2+ from intracellular stores. Thus, inhibition of CD38 provides a promising new approach to improve the recovery of endothelial function in the postischemic heart.
- © 2011 by American Heart Association, Inc.