NAD+ Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy

Abstract

BackgroundDiabetes is a risk factor of heart failure and promotes cardiac dysfunction. Diabetic tissues are associated with NAD+ redox imbalance; however, the hypothesis that NAD+ redox imbalance leads to dysfunction of diabetic hearts has not been tested. In this study, we employed mouse models with altered NAD+ redox balance to test the hypothesis. Methods and ResultsDiabetes was induced in C57BL/6 mice by streptozotocin injections, and diabetic cardiomyopathy (DCM) was allowed to develop for 16 weeks. Diabetic stress led to cardiac dysfunction and lowered NAD+/NADH ratio. This diabetogenic regimen was administered to cardiac-specific knockout mice of complex I subunit Ndufs4 (cKO), a model with lowered cardiac NAD+/NADH ratio without baseline dysfunction. Cardiac NAD+ redox imbalance in cKO hearts exacerbated systolic and diastolic dysfunction of diabetic mice in both sexes. Collagen levels and transcript analyses of fibrosis and extracellular matrix-dependent pathways did not show change in diabetic cKO hearts, suggesting that the exacerbated cardiac dysfunction was likely due to cardiomyocyte dysfunction. We found that cardiac NAD+ redox imbalance promoted superoxide dismutase 2 (SOD2) acetylation, protein oxidation, induced troponin I S150 phosphorylation and impaired energetics in diabetic cKO hearts. Importantly, elevation of cardiac NAD+ levels by nicotinamide phosphoribosyltransferase (NAMPT) normalized NAD+ redox balance, over-expression alleviated cardiac dysfunction and reversed pathogenic mechanisms in diabetic mice. ConclusionOur results show that NAD+ redox imbalance to regulate protein acetylation and phosphorylation is a critical mediator of the progression of DCM, and suggest the therapeutic potential of harnessing NAD+ metabolism in DCM.