PT  - JOURNAL ARTICLE
AU  - James Boslett
AU  - Craig Hemann
AU  - Y J Zhao
AU  - Hon-Cheung Lee
AU  - Jay L Zweier
TI  - Luteolinidin protects the post-ischemic heart through CD38 inhibition with preservation of NAD(P)(H)
AID  - 10.1124/jpet.116.239459
DP  - 2017 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.116.239459
4099  - http://jpet.aspetjournals.org/content/early/2017/01/20/jpet.116.239459.short
4100  - http://jpet.aspetjournals.org/content/early/2017/01/20/jpet.116.239459.full
AB  - Recently, we have shown that ischemia and reperfusion (I/R) of the heart causes CD38 activation with resultant depletion of the cardiac NADP(H) pool, most marked in the endothelium. This NADP(H) depletion was shown to limit the production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS), which requires NADPH for NO production, resulting in greatly altered endothelial function. Therefore, intervention with CD38 inhibitors could reverse post-ischemic eNOS-mediated endothelial dysfunction. We evaluate the potency of the CD38 inhibitor luteolinidin, an anthocyanidin, at blocking CD38 activity and preserving endothelial and myocardial function in the post-ischemic heart. Initially, we characterize luteolinidin as a CD38 inhibitor in vitro to determine its potency and mechanism of inhibition. We then test 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 post-ischemic NAD(P)(H) and tetrahydrobiopterin (BH4) levels. Lastly, through NOS-dependent coronary flow and left ventricular (LV) functional measurements, we evaluated the efficacy of luteolinidin to protect vascular and contractile function, respectively, after I/R. With enhanced post-ischemic preservation of NADPH and BH4, 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, luteolindin is a potent CD38 inhibitor that protects the heart against I/R injury with preservation of eNOS function and prevention of endothelial dysfunction.