Abstract 409: Ablation of Endothelial Sirt3 Exacerbates Pressure Overload-induced Heart Failure

Abstract

Cardiovascular disease leads to cardiac dysfunction and eventually heart failure which is the leading cause of death in the United States. Our previous data indicates that global ablation of SIRT3 exacerbates acute injury after myocardial ischemia and that deletion of endothelial SIRT3 (SIRT3 ECKO) leads to development of cardiac dysfunction. In the present study, we demonstrates that loss of SIRT3 in endothelial cells results in upregulation of TIGAR, but downregulation of HIF-1α, HIF-2α, glucose transport GLUT-1, glycolytic enzymes PFK-1, and PFKFB3. To further investigate the role of endothelial SIRT3 on cardiac hypertrophy and heart failure during chronic stress, SIRT3 ECKO and their control SIRT3 LoxP mice were subjected to pressure overload-induced by transverse aortic constriction (TAC) for 7 weeks. Our results demonstrate that the ratio of heart weight to tibia length was increased in both strains of mice, in which SIRT3 ECKO + TAC mice exhibited more severe cardiac hypertrophy. In addition, systolic function was significantly decreased in SIRT3 ECKO + TAC mice compared to SIRT3 LoxP + TAC mice, as evidenced by lower EF and FS at week 7. In contrast, diastolic function decreased after TAC surgery in a similar manner in both strains of mice, despite that pre-existing diastolic dysfunction was found in SIRT3 ECKO mice. Similarly, there was no difference in coronary flow reserve between both strains of mice subjected to TAC. Moreover, pressure overload-induced upregulation of Apelin, Angiopoietin-1, GLUT-4, and ERK phosphorylation were decreased in SIRT3 ECKO + TAC mice, whereas the expression of pro-inflammatory molecules, ICAM-1 and VCAM-1, was significantly increased in SIRT3 ECKO + TAC mice. These results implicate a critical role of SIRT3 in regulating glucose uptake and glycolytic function in endothelial cells. Ablation of endothelial SIRT3 exacerbates pressure overload-induced cardiac hypertrophy and heart failure via impaired glucose metabolism and increased pro-inflammatory molecules.