Abstract
The incidences of heart failure with preserved ejection fraction (HFpEF) are increased in aged populations as well as diabetes and hypertension. Coronary microvascular dysfunction has contributed to the development of HFpEF. Endothelial cells (ECs) depend on glycolysis rather than oxidative phosphorylation for generating adenosine triphosphate to maintain vascular homeostasis. Glycolytic metabolism has a critical role in the process of angiogenesis, because ECs rely on the energy produced predominantly from glycolysis for migration and proliferation. Sirtuin 3 (SIRT3) is found predominantly in mitochondria and its expression declines progressively with aging, diabetes, obesity, and hypertension. Emerging evidence indicates that endothelial SIRT3 regulates a metabolic switch between glycolysis and mitochondrial respiration. SIRT3 deficiency in EC resulted in a significant decrease in glycolysis, whereas, it exhibited higher mitochondrial respiration and more prominent production of reactive oxygen species. SIRT3 deficiency also displayed striking increases in acetylation of p53, EC apoptosis, and senescence. Impairment of SIRT3-mediated EC metabolism may lead to a disruption of EC/pericyte/cardiomyocyte communications and coronary microvascular rarefaction, which promotes cardiomyocyte hypoxia, Titin-based cardiomyocyte stiffness, and myocardial fibrosis, thus leading to a diastolic dysfunction and HFpEF. This review summarizes current knowledge of SIRT3 in EC metabolic reprograming, EC/pericyte interactions, coronary microvascular dysfunction, and HFpEF.