Nampt Potentiates Antioxidant Defense in Diabetic Cardiomyopathy

Abstract

Rationale: Diabetic cardiomyopathy is accompanied by increased production of NADH, predominantly through oxidation of fatty acids and consequent increases in oxidative stress. The role of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme of the salvage pathway of NAD + synthesis, in the development of diabetic cardiomyopathy is poorly understood. Objective: We investigated the role of endogenous and exogenous Nampt during the development of diabetic cardiomyopathy in response to high fat diet (HFD) consumption and in the context of oxidative stress. Methods and Results: HFD consumption upregulated endogenous Nampt, and HFD-induced cardiac diastolic dysfunction, fibrosis, apoptosis and pro-inflammatory signaling were alleviated in transgenic mice with cardiac-specific overexpression of Nampt. The alleviation of diastolic dysfunction observed in these mice was abolished by inhibition of NADP(H) production via NAD kinase (NADK) inhibition. Nampt overexpression decreased the GSSG/GSH ratio, oxidation of thioredoxin 1 (Trx1) targets, dityrosine, and the accumulation of toxic lipids, including ceramides and diglycerides, in the presence of HFD consumption. Nampt overexpression upregulated not only NAD + but also NADP + and NADPH in the heart and in cultured cardiomyocytes, which in turn stimulated the GSH and Trx1 systems and alleviated oxidative stress in the heart induced by HFD consumption. In cultured cardiomyocytes, Nampt-induced upregulation of NADPH was abolished in the presence of NADK knockdown, whereas that of NAD + was not. Nampt overexpression attenuated H 2 O 2 -induced oxidative inhibition of Prdx1 and mTOR in an NADK-dependent manner in cultured cardiomyocytes. Nampt overexpression also attenuated H 2 O 2 -induced cell death, an effect that was partly abolished by inhibition of NADK, Trx1 or GSH synthesis. In contrast, oxidative stress and the development of diabetic cardiomyopathy in response to HFD consumption were exacerbated in Nampt +/- mice. Conclusions: Nampt-mediated production of NAD + protects against oxidative stress in part through the NADPH-dependent reducing system, thereby alleviating the development of diabetic cardiomyopathy in response to HFD consumption.