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Background: Diabetes is a risk factor for heart failure and promotes cardiac dysfunction. Diabetic tissues are associated with nicotinamide adenine dinucleotide (NAD + ) redox imbalance; however, the hypothesis that NAD + redox imbalance causes diabetic cardiomyopathy has not been tested. This investigation used mouse models with altered NAD + redox balance to test this hypothesis. Methods: Diabetic stress was induced in mice by streptozotocin. Cardiac function was measured by echocardiography. Heart and plasma samples were collected for biochemical, histological, and molecular analyses. Two mouse models with altered NAD + redox states (1, Ndufs4 [NADH:ubiquinone oxidoreductase subunit S4] knockout, cKO, and 2, NAMPT [nicotinamide phosphoribosyltranferase] transgenic mice, NMAPT) were used. Results: Diabetic stress caused cardiac dysfunction and lowered NAD + /NADH ratio (oxidized/reduced ratio of nicotinamide adenine dinucleotide) in wild-type mice. Mice with lowered cardiac NAD + /NADH ratio without baseline dysfunction, cKO mice, were challenged with chronic diabetic stress. NAD + redox imbalance in cKO hearts exacerbated systolic (fractional shortening: 27.6% versus 36.9% at 4 weeks, male cohort P <0.05), and diastolic dysfunction (early-to-late ratio of peak diastolic velocity: 0.99 versus 1.20, P <0.05) of diabetic mice in both sexes. Collagen levels and transcripts of fibrosis and extracellular matrix–dependent pathways did not show changes in diabetic cKO hearts, suggesting that the exacerbated cardiac dysfunction was due to cardiomyocyte dysfunction. NAD + redox imbalance promoted superoxide dismutase 2 acetylation, protein oxidation, troponin I S150 phosphorylation, and impaired energetics in diabetic cKO hearts. Importantly, elevation of cardiac NAD + levels by NAMPT normalized NAD + redox balance, alleviated cardiac dysfunction (fractional shortening: 40.2% versus 24.8% in cKO:NAMPT versus cKO, P <0.05; early-to-late ratio of peak diastolic velocity: 1.32 versus 1.04, P <0.05), and reversed pathogenic mechanisms in diabetic mice. Conclusions: Our results show that NAD + redox imbalance to regulate acetylation and phosphorylation is a critical mediator of the progression of diabetic cardiomyopathy and suggest the therapeutic potential for diabetic cardiomyopathy by harnessing NAD + metabolism.

Background and Purpose Kinase inhibitors are a common treatment for cancer. Class I kinase inhibitors that target the ATP‐binding pocket are particularly prevalent. Many of these compounds are cardiotoxic and can cause arrhythmias. Spontaneous release of Ca2+ via cardiac ryanodine receptors (RyR2), through a process termed store overload‐induced Ca2+ release (SOICR), is a common mechanism underlying arrhythmia. We explored whether class I kinase inhibitors could modify the activity of RyR2 and trigger SOICR to determine if this contributes to the cardiotoxic nature of these compounds. Experimental Approach The impact of class I and II kinase inhibitors on SOICR was studied in HEK293 cells and ventricular myocytes using single‐cell Ca2+ imaging. A specific effect on RyR2 was confirmed using single channel recordings. Ventricular myocytes were also used to determine if drug‐induced changes in SOICR could be reversed using anti‐SOICR agents. Key Results Class I kinase inhibitors increased the propensity of SOICR. Single channel recording showed that this was due to a specific effect on RyR2. Class II kinase inhibitors decreased the activity of RyR2 at the single channel level but had little effect on SOICR. The promotion of SOICR mediated by class I kinase inhibitors could be reversed using the anti‐SOICR agent VK‐II‐86. Conclusions and Implications Part of the cardiotoxicity of class I kinase inhibitors can be assigned to their effect on RyR2 and increase in SOICR. Compounds with anti‐SOICR activity may represent an improved treatment option for patients.

AbstractBackgroundDiabetes is a risk factor of heart failure, and chronic diabetic stress leads to 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 and to characterize the underlying mechanism.Methods and ResultsType 1 diabetes was induced in C57/BL6 mice by streptozotocin injections, and diabetic cardiomyopathy (DCM) was allowed to develop for 16-weeks. Chronic diabetic stress led to cardiac dysfunction and lowered NAD+/NADH ratio. The same diabetogenic regimen was administered to cardiac-specific Ndufs4-KO mice (cKO), a model of lowered cardiac NAD+/NADH ratio without overt 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 showed no 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 SOD2 acetylation and protein oxidation, and regulated TnI phosphorylation in diabetic cKO hearts. Elevation of cardiac NAD+ levels by NAMPT over-expression mitigated NAD+ redox imbalance in diabetic cKO mice, reversed SOD2 acetylation and TnI phosphorylation, and alleviated cardiac dysfunction.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.

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