Abstract Body: INTRODUCTION: Heart failure (HF) is the leading cause of death in the United States, despite advances in treatment, it maintains the highest disease mortality rate in the country. Previously it has been established that Sirtuin 3 (SIRT3), a mitochondrial NAD+- dependent deacetylase, and the Tp53-induced glycolysis and apoptosis regulator (TIGAR) are associated with the development of HF. SIRT3 plays a key role in the maintenance of cardiac function. Decreases in SIRT3 are associated with human aging and diabetes, whereas knockout results in cardiac dysfunction in mice. We have shown: (1) overexpression of SIRT3 downregulates TIGAR and attenuates diabetic cardiomyopathy; (2) knockout of TIGAR enhances myocardial glycolysis and reduces pathological remodeling while maintaining cardiac function in pressure-overload-induced heart failure. To date, the direct interactions between TIGAR and SIRT3 in the development of HF remain unexplored.

AIM: By crossing TIGAR knockout mice (TIGARKO) with SIRT3 knockout (SIRT3KO) mice, this study tested if genetic targeting of TIGAR could rescue cardiac dysfunction in SIRT3KO mice.

METHODS AND RESULTS: Echocardiography was performed on SIRT3KO, TIGARKO, TIGARKO/SIRT3KO, and SIRT3 Control mice. Analysis of cardiac function showed that SIRT3KO mice had significant decreases in coronary flow reserve (CFR), ejection fraction (EF) SIRT3KO (41.52 ± 4.50) vs SIRT3 Control (60.91 ± 4.91, p<0.001) and fractional shortening (FS) SIRT3KO (20.11 ± 2.48) vs SIRT3 Control (32.07 ± 3.37, p<0.001). The diastolic E’/A’ ratio was decreased; IVRT and MPI were significantly increased. Knockout of TIGAR in mice maintained systolic function by increasing EF (62.25 ± 9.84) vs (41.52 ± 4.50, p<0.001), FS (33.33 ± 7.12 vs 20.11 ± 2.48, p<0.05), and CFR, as well as improved diastolic function by decreasing IVRT, MPI, and increasing E’/A’ ratio in SIRT3KO mice. SIRT3KO and TIGARKO mice had a significant increase in weight/tibia length ratio (HW/TL). Interestingly, the knockout of TIGAR significantly reduced LV mass and HW/TL in SIRT3KO mice.

CONCLUSIONS: The knockout of TIGAR can rescue the HF phenotype of SIRT3KO mice, but the underlying mechanisms require further investigation to develop potential treatments for HF.