Abstract 394: Nicotinamide Phosphoribosyltransferase (Nampt) Potentiates Antioxidant Defense in Diastolic Heart Failure Associated With Diabetes

Abstract

More than half of diabetic patients develop diastolic heart failure. Nampt is a rate-limiting enzyme for NAD synthesis. Phosphorylation of NAD by NAD kinase (NADK) generates NAD phosphate (NADP), which is in turn converted to NADPH and provides the GSH and thioredoxin (Trx) systems with a reducing power. Whether Nampt is protective against diabetic cardiomyopathy (DCM) and, if so, whether NADK mediates the salutary function of Nampt are unknown. We employed mice with cardiac-specific Nampt overexpression (Nampt-cTG) and a mouse model of DCM induced by high fat diet (HFD) consumption. HFD-induced diastolic dysfunction, indicated by an elevated end-diastolic pressure-volume relationship (EDPVR), was ameliorated in Nampt-cTG mice (EDPVR: wild-type mice (WT) Normal Diet (ND): 0.045; WT HFD (1 month): 0.136; Nampt-cTG: 0.042: Nampt-cTG HFD: 0.055*, p<0.05 vs WT HFD). The protective effect was abolished by thionicotinamide, an NADK inhibitor (EDPVR: Nampt-cKO HFD with thionicotinamide 0.12*, p<0.05 vs Nampt-cKO HFD). Nampt overexpression also attenuated HFD-induced increases in GSSG/GSH and oxidation of Trx1 substrates, including peroxiredoxin 1 (Prdx1). Nampt overexpression upregulated not only NAD(H) (1.5 fold) but also NADP(H) (1.3 fold) in the heart and in cardiomyocytes. Nampt-induced NADPH upregulation was abolished in the presence of NADK knockdown. Nampt attenuated H 2 O 2 -induced oxidation of Trx1 substrates in an NADK-dependent manner in cardiomyocytes. Nampt overexpression inhibited H 2 O 2 -induced cell death, an effect that was attenuated in the presence of NADK inhibition. Systemic Nampt heterozygous knockout promoted HFD-induced diastolic dysfunction and oxidative stress in the heart in vivo . These results suggest that Nampt protects the heart against diastolic dysfunction through upregulation of the reducing system, which occurs through NADK-dependent upregulation of the reducing equivalent, namely NADPH.