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 Cardioprotective effects of P7C3 in diabetic hearts via Nampt activation.


Diabetes is associated with increased cardiac injury and sudden death. Nicotinamide phosphoribosyltransferase (Nampt) is an essential enzyme for the NAD+ salvage pathway and dysregulated in diabetes. Hypothesis: Nampt activation results in rescued NADH/NAD+ ratios and provides pharmacological changes necessary for diabetic cardioprotection. Computer docking shows that P7C3 allows for enhanced Nampt dimerization and association. Methods: To test the pharmacological application, we utilized male leptin receptor-deficient (db/db) mice and treated with Nampt activator P7C3 (1-(3,6-Dibromo-carbazol-9-yl)-3-phenylamino-propan-2-ol). The effects of four-week P7C3 treatment on cardiac function were evaluated along with molecular signaling changes for p-AKT, p-eNOS, and SiRT-1. Results: The cardiac function evaluated by ECG and Echo were significantly improved after four-weeks of P7C3 treatment. Biochemically, higher NADH/NAD+ ratio in diabetic heart were rescued by P7C3 treatment. Moreover, activities of Nampt and Sirt1 were significantly increased in P7C3 treated diabetic hearts. P7C3 treatment significantly decreased the blood glucose in diabetic mice with 4-week treatment as noted by glucose tolerance test and fasting blood glucose measurements compared with vehicle treated mice. P7C3 activated Nampt enzymatic activity both in vitro and in the 4-week diabetic mouse hearts demonstrates the specificity of the small molecule. P7C3 treatment significantly enhanced the expression of cardioprotective signaling; p-AKT, p-eNOS, and Beclin 1 in diabetic hearts. Nampt activator P7C3 allows for decreased infarct size with decreased Troponin I and LDH release, which is beneficial to the heart. Conclusions: Overall, the present study shows that P7C3 activates Nampt and Sirt1 activity, decreases NADH/NAD+ ratio, resulting in improved biochemical signaling providing cardioprotection. Significance Statement We show that P7C3 is effective in the treatment of diabetes and cardiovascular diseases. The novel small molecule is anti-arrhythmic and improves the ejection fraction in diabetic hearts. The study demonstrates that P7C3 decreases the infarct size in heart during myocardial infarction and ischemia-reperfusion injury. Biochemical and cellular signaling show increased NAD+ levels, along with Nampt activity involved in upregulating protective signaling in the diabetic heart. Based on the cardioprotective properties P7C3 has high therapeutic potential.