Abstract 20167: The CD38 Inhibitor Luteolinidin Ameliorates Ischemia/reperfusion Injury Through Preservation of NADP(H) and NAD(H)
Introduction: In postischemic hearts impaired endothelial function occurs with endothelial nitric oxide synthase (eNOS) dysfunction limiting vasodilation and tissue perfusion. We have observed that during cardiac ischemia/reperfusion (I/R), the eNOS substrate NADPH is depleted with >80% loss in the endothelium and NADPH repletion restores eNOS activity and vasodilation. To determine the mechanism of NADPH depletion, the NAD(P)-consuming enzyme CD38 was investigated. There has been a need for a potent and specific CD38 inhibitor. Recently, the flavonoid luteolinidin has been shown to inhibit CD38 in the low μM range. We hypothesized that luteolindin as a potent CD38 inhibitor would elicit protection of endothelial and myocardial function in the postischemic heart.
Methods: Isolated Langendorff perfused rat hearts were treated with luteolinidin (50 μM) (n=8) or vehicle control (n=10) and subjected to 30 min I and 30 min R. Contractile function was measured by intraventricular balloon, and coronary flow by Doppler flow probe. After 30 min R, hearts were frozen for high performance liquid chromatography (HPLC) of NADP(H) and NAD(H). NOS-dependent coronary flow (NDCF) was measured using 1 mM L-NAME.
Results: With luteolinidin pretreatment, hearts subjected to 30 min I had higher recovery of NADP(H) and NAD(H) (54.6 +/- 6.8% and 55.1 +/- 5.8% higher), enhanced recovery of NDCF (49.5 +/-5.4% higher), and higher recovery of contractile function upon R compared to vehicle control hearts (fig. & table).
Conclusion: Luteolinidin was shown to inhibit CD38 preserving NADP(H) and NAD(H) pools, and providing endothelial and myocardial protection of the postischemic heart.
Author Disclosures: J.J. Boslett: None. F. De Pascali: None. C. Hemann: None. J. Zweier: None.
- © 2014 by American Heart Association, Inc.