1. NAD + Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy
- Author
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Junichi Sadoshima, Akash Deep Chakraborty, Chi Fung Lee, Rong Tian, Haiwei Gu, Christine Light, Xiaojian Shi, and Ying Ann Chiao
- Subjects
medicine.medical_specialty ,business.industry ,SOD2 ,Nicotinamide phosphoribosyltransferase ,Cardiomyopathy ,Nicotinamide adenine dinucleotide ,Protein oxidation ,medicine.disease ,Redox ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Internal medicine ,Diabetic cardiomyopathy ,Heart failure ,Diabetes mellitus ,Knockout mouse ,medicine ,NAD+ kinase ,Risk factor ,Cardiology and Cardiovascular Medicine ,business - Abstract
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 P + 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 P 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.
- Published
- 2021
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