Abstract P3046: Deletion Of Sarm1 Nad Hydrolase Ameliorates Diabetic Cardiomyopathy

Abstract

Diabetes is a risk factor for heart disease. NAD depletion has emerged as a hallmark of cardiometabolic diseases, and hence, elevating NAD level alleviates diabetic cardiomyopathy. On the other hand, inhibition of NAD consumption also maintains NAD homeostasis. SARM1 is a novel intracellular NAD hydrolase that contributes to diabetic neuropathy; however, its role in heart disease has never been described. We assayed 243 plasma metabolites from wild-type (WT) and SARM1-KO (KO) mice by quantitative metabolomics, and found that SARM1 deficiency caused changes in more (67) metabolites in male mice than in female mice (28). Only 5 of these metabolites overlapped between male and female, indicating sex-dependent effect of SARM1 deletion on plasma metabolites. SARM1 deficiency may alter susceptibility of male mice to metabolic stress, since metabolites associated with diabetes and impaired metabolism were altered, e.g. pyridoxic acid, alloisoleucine, LPC/PC, ceramide etc. Despite the differences in plasma metabolite levels, KO mice from either sex did not show changes in cardiac structure and function at baseline. We next tested a hypothesis that SARM1 deficiency protects mice against diabetic cardiomyopathy. WT and KO mice were challenged with streptozotocin (STZ) to induce diabetic stress. 16-week diabetes promoted progressive systolic (fractional shortening) and diastolic dysfunction (E’/A’, e/E’) in WT male mice. SARM1 deficiency attenuated diabetes-induced cardiac dysfunction, although fasting glucose levels were similarly elevated in diabetic WT and KO mice. Diabetic WT hearts showed declined NAD level, which was elevated by SARM1 deficiency. The restored NAD level in KO hearts did not change expression of other NAD hydrolases (Bst1 and CD38). Diabetic WT hearts up-regulated cardiomyopathy markers such as nppb and Nox4 mRNAs, and myh7/myh6 ratio, that were normalized by SARM1 deficiency. Chronic diabetes promoted cardiac fibrosis and upregulation of profibrotic gene expression such as ctgf and Inhbb, that were suppressed by SARM1 deficiency. Our data suggest a protective effect of SARM1 deficiency on diabetic cardiomyopathy in male mice. The effects of SARM1 deficiency on diabetic hearts could be sex-dependent and remain to be determined.