Abstract 13316: Cardiomyopathy Induced by Metabolic and Hypertensive Stresses is Alleviated by SARM1 Deficiency

Abstract

Introduction: NAD depletion emerges as a hallmark of diseases. Strategies to replenish NAD levels have shown promise to treat heart disease, including heart failure with preserved ejection fraction (HFpEF). However, how NAD consumption mechanisms lead to NAD depletion are less understood. SARM1 is a novel intracellular NAD hydrolase that promotes axonal degeneration after axon injury, and its role in cardiomyopathy has not been tested. Hypothesis: We hypothesized that SARM1 deficiency will protect hearts against cardiomyopathy induced by metabolic and hypertensive stresses. Methods and Results: Aged-matched male C57BL/6 wild type (WT) and whole-body SARM1-KO mice were challenged with 16-week diabetic stress initiated by streptozotocin (STZ). SARM1 mRNA or protein levels were suppressed in KO hearts. STZ induced similar hyperglycemia (~600 mg/dL) in both WT and KO mice after 16 weeks. Chronic diabetic stress led to progressive decline in systolic function (FS: 50% vs 35%; P<0.05; n=5) in WT mice, which was ameliorated in KO mice (48%; P<0.05; n=5). Progressive decline in diastolic function by chronic diabetes (E’/A’: 1.53 vs 1.12; n=5) was also improved in diabetic KO mice (1.5; P<0.05; n=5). Up-regulated Nppb in diabetic WT hearts was suppressed by SARM1 deficiency. No compensatory changes in expressions of other NAD hydrolases were observed in diabetic KO hearts. Cardiac fibrosis was induced in diabetic WT hearts and were suppressed in diabetic KO hearts after 16-week diabetic stress. WT and KO mice were challenged with high fat diet feeding (HFD) or HFD with L-NAME (a HFpEF regimen) for 16 weeks. Systolic function was unchanged in mice after HFD or HFpEF regimen, with or without SARM1 deficiency. However, SARM1 deficiency ameliorated diastolic dysfunction of male mice induced by HFD (WT vs KO E’/A’ = 1.07 vs 1.37, n=5) or HFpEF regimen (WT vs KO E’/A’ = 0.96 vs 1.31, n=6). Unlike diabetic cardiomyopathy induced by STZ, cardiac hypertrophy in WT mice was induced by HFD or HFpEF regimen, and KO mice showed decreases in hypertrophy induced by the two stressors. Conclusion: Our data support a protective role of SARM1 deficiency in cardiomyopathy. Pathogenic mechanisms of SARM1 in cardiomyopathy induced by metabolic or hypertensive stresses remain to be determined.