Abstract 14798: NAMPT Inhibition Restores Coronary Microvascular Dysfunction in Diabetes

Abstract

Introduction: Nicotinamide phosphoribosyltransferase (NAMPT) is a multitask peptide; extracellular NAMPT acts as a proinflammatory cytokine, and intracellular NAMPT participates in energy metabolism through NAD + production. Serum NAMPT level is increased in diabetic patients; however, the pathophysiological role of NAMPT in diabetic cardiovascular complications is poorly understood. This study aims to investigate the effect of NAMPT inhibition on coronary microvascular function in diabetes. Materials and Methods: We used two diabetic mouse models: inducible type 2 diabetic (T2D) mice generated by a single injection of low-dose STZ (75 mg/kg, i.p.) with a high-fat diet feeding, and spontaneous T2D mice, TALLYHO/JngJ. Cardiac endothelial cells (CECs) were isolated for molecular biological experiments. Coronary flow velocity reserve (CFVR) was used to determine coronary microvascular function. Results: T2D mice exhibited elevated NAMPT expression in CECs. There was no difference in glucose tolerance and body weight in diabetic NAMPT hetero knockout mice and FK866 (NAMPT inhibitor)-administered diabetic mice compared to their controls. However, CFVR was significantly increased by NAMPT inhibition in T2D mice, accompanied by increased capillary density and augmented endothelium-dependent relaxation (EDR). Chronic administration of neutralizing NAMPT antibody (Ab) also improved CFVR in T2D mice toward the level in control mice. RNA sequencing data in CECs revealed that NAMPT-Ab administration in T2D mice significantly restored the levels of genes related to angiogenesis. NAMPT (100 ng/ml) or NAD + (100 nM) treatment attenuated cell migration in control CECs and reduced EDR in control CAs. Furthermore, NAMPT or NAD + treatment increased mitochondrial ROS formation and decreased Gap junction activity in control CECs. Conclusion: Our data suggest that NAMPT inhibition increases capillary density via enhancing endothelial migration, arguments EDR through reducing mitochondrial ROS production and increasing gap junction activity, and results in restoration of coronary microvascular function in diabetic mice. Therefore, NAMPT inhibition could be a new therapeutic strategy for coronary microvascular disease in diabetes.