NAD ⁺ Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy

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 <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.

Impact of circadian time of dosing on cardiomyocyte-autonomous effects of glucocorticoids

“…Our study found notable effects on both NAD + and mitochondrial respiration/abundance in myocardial tissue, suggesting a comprehensive positive effect of light-phase prednisone on aerobic energy production in heart. Moreover, the effects of light-phase prednisone on Nampt upregulation and NAD + biogenesis in heart are consistent with the positive effects of NAD + replenishment in heart failure [ 19 , 44 , 45 , 51 ]. However, our study was performed in male mice and additional studies are required to address whether effect size and mechanisms are replicable in female mice.…”

“…Perhaps of importance for cardiac metabolism, here we found that the NAD + increase induced by light-phase prednisone treatments correlated with decreased ROS production in normal and infarcted myocardium. Several reports have recently focused on direct effects of NAD + redox state on oxidative stress in conditions of diabetic heart failure [ 44 , 45 ]. Our data cannot discriminate between NAD + repletion versus mitochondrial rescue as main promoter of ROS decrease downstream of light-phase prednisone, and dedicated studies will likely shed light on this pathway.…”

Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome

“…Our data appear to resolve some mysteries that have persisted in the study of LS. In particular: 1) Why is there a general sparing of some tissues with high energy requirements, as in cardiac-specific Ndufs4 (KO) in the absence of a stressor ( 60 – 62 )? If disease sequelae are mediated by immune responses, tissue energetics may not play a direct role.…”

Ameliorative effects of chickpea flavonoids on redox imbalance and mitochondrial complex I dysfunction in type 2 diabetic rats

“…Studies have claimed that there is NAD + /NADH redox imbalance in the diabetic pancreas and lungs. 32,33 After treatment with CCFE, the NAD + /NADH ratio in the CCFE-M and CCFE-H groups significantly increased ( p < 0.05) compared with that in the DM control group, which confirmed that the NAD + /NADH redox imbalance in the pancreas of T2DM rats was alleviated by CCFE. Moreover, Ogura et al 34 found that apigenin increased the intracellular NAD + /NADH ratio in the kidneys of diabetic rats by inhibiting the CD38 activity.…”