Abstract P3039: NAD Redox Imbalance Exacerbates Diabetic Cardiomyopathy, Regulates Nmrk2 Expression And Alters NAD Synthesis

Abstract

Heart failure occurs at twice the rate in diabetic patients compared to normal subjects. NAD redox imbalance or depletion has emerged as a hallmark of diabetes and heart disease. We showed that NAD redox imbalance or depletion promotes heart failure progression, but its role in diabetic cardiomyopathy has not been established. We used two mouse models with altered NAD metabolism. 1. Cardiac-specific NDUFS4-KO (cKO) mice which have mitochondrial complex I deficiency, decreased NAD/NADH ratio, but normal baseline cardiac function and energetics. 2. Cardiac-specific overexpression of nicotinamide phosphoribosyltransferase (NAMPT) in mice which elevates cardiac NAD levels. Diabetic stress induced by streptozotocin (STZ) promoted systolic (fractional shortening) and diastolic (E’/A’, e/E’) dysfunction, which were exacerbated in cKO mice. Overexpression of NAMPT to reverse NAD redox imbalance ameliorated cardiac dysfunction in both diabetic control and diabetic cKO mice. We measured expression levels of 58 genes related to NAD metabolism in these diabetic hearts. Transcript levels of genes for NAD consumption (sirtuins, PARPs and hydrolases) and NAD synthesis pathways (including NMRK1) did not change, except Nicotinamide Riboside Kinase 2 (NMRK2). NMRK2 transcript was upregulated in diabetic cKO hearts, associated with a decline in NAD levels. Expression of NAMPT to elevate NAD levels downregulated NMRK2 expression in both treated and untreated mice. The data indicate that upregulation of NMRK2 transcript is negatively correlated with cardiac function and NAD levels. NMRK2 is an enzyme involved in the Preiss-Handler and Salvage pathways of NAD synthesis by phosphorylating the NAD precursor Nicotinamide Riboside (NR) into Nicotinamide Mononucleotide (NMN). NAD metabolite analysis in the heart tissue showed a trended increase in the substrate of NMRK2, NR, and a trended decrease in the products, NMN or NAMN in diabetic cKO hearts with a decline in NAD levels. Our results suggest that NAD redox imbalance drives the progression of diabetic cardiomyopathy, and NMRK2 upregulation may regulate disease progression and NAD synthesis through mechanisms to be determined.