Deletion of Endothelial SIRT3 Causes Coronary Microvascular Dysfunction and HFpEF

Abstract

The morbidity of heart failure with preserved ejection fraction (HFpEF) increases with advanced age and diabetes, and is associated with endothelial dysfunction. SIRT3, a mitochondrial NAD+‐dependent deacetylase, declines progressively with aging and in diabetes. However, the role of SIRT3 reduction in HFpEF remains to be elucidated. In the present study, we analyzed the cardiac function and coronary microvascular function in endothelial specific SIRT3 knockout (ECKO) mice and global SIRT3 KO mice, as well as endothelial glycolytic metabolism and angiogenesis in vitro. We found that SIRT3 ECKO mice developed left ventricle (LV) diastolic dysfunction, as evidenced by prolonged isovolumic relaxation time (IVRT) and reduction of coronary flow reserve. Western blot analysis revealed a significant decrease in glycolytic enzyme PFKFB3 in SIRT3 KO‐ECs, accompanied by a dramatic reduction in basal glycolysis, glycolytic reserve and glycolytic capacity. Moreover, SIRT3 KO‐ECs exhibited higher oxygen consumption rate and more prominent production of reactive oxygen species (ROS) than WT‐ECs. SIRT3 KO‐ECs exhibited less potent angiogenic capabilities as indicated by decreased network formation and migration. In contrast, global knockout of SIRT3 in mice resulted in progressive deterioration of LV function, as evidenced by a decrease in ejection fraction and fraction shortening at 12 months of age. SIRT3 KO mice also exhibited reduction of ANP and ERK‐1/2, and increased ROS production, gp91(phox), caspase‐3 and Wnt7 in the heart. In conclusion, we demonstrated that ablation of SIRT3 in ECs caused an HFpEF phenotype with impaired glucose metabolism and angiogenesis. Global SIRT3 KO mice, however, exhibited an HFrEF phenotype. Our data suggest cell‐specific effects of SIRT3 deletion on cardiac function.Support or Funding InformationThis study was supported by National Institutes of Health RO1 HL102042 (Chen).