Abstract 858: NAD(H) Redox Imbalance in the Heart Accelerates Diabetic Cardiomyopathy

Abstract

Diabetes is linked to NAD(H) redox imbalance and lowered NAD + levels, but the roles of NAD + metabolism in diabetic cardiomyopathy are not established. We induced diabetes in C57BL6 wild type mice (WT) by streptozotocin (STZ) injections to cause depletion in serum insulin levels and elevation in fasting glucose levels. Hyperglycemic, male WT mice showed gradual declines in systolic and diastolic functions (FS, 50% vs 30%; E’/A’ ratio, 1.5 vs 1.0; 16-week after STZ), without causing cardiac hypertrophy. Dysfunctions in diabetic hearts were associated with lowered NAD + /NADH ratio and protein hyperacetylation, suggesting the roles of NAD(H) redox imbalance in diabetic cardiomyopathy. To test if NAD(H) redox imbalance promotes dysfunctions of diabetic hearts, we employed cardiac-specific Ndufs4-KO mice (cKO), which exhibit lowered NAD + /NADH ratio without overt cardiac dysfunction at baseline. Changes in cardiac functions at 2-, 4-, and 8-week after STZ injections, insulin and fasting glucose levels of control and cKO male mice were measured. Similar insulin depletion and hyperglycemia (~450 mg/dL) were observed in diabetic control and cKO mice. Systolic and diastolic dysfunctions were worsened in diabetic cKO mice (control vs cKO: FS 37% vs 22%; E’/A’ 1.25 vs 0.95, 8-week after STZ). Cardiac fibrosis levels were slightly elevated in diabetic control and cKO hearts, but were not different between the two groups (~4% in both group of mice). The results suggested that the accelerated declines in cardiac functions contributed by NAD(H) redox imbalance are not due to the altered extracellular matrix environment. To restore the NAD(H) redox balance in diabetic hearts, we elevated NAD + levels in male control and cKO mice with cardiac-specific NAMPT overexpression. Elevations in cardiac NAD + levels alleviated systolic and diastolic dysfunctions in diabetic control and cKO mice, despite similar levels of hyperglycemia among groups. Similar exacerbation of cardiac dysfunction was observed in female diabetic cKO mice, while NAMPT overexpression similarly improved cardiac function in female diabetic control and cKO mice. Our findings showed that NAD(H) redox imbalance promotes the progression of diabetic cardiomyopathy, via a fibrosis-independent mechanism.