Sirtuin 3, Endothelial Metabolic Reprogramming, and Heart Failure With Preserved Ejection Fraction

Area of Science:

• Cardiovascular Biology
• Mitochondrial Metabolism
• Cellular Aging

Background:

• Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent in aging populations, particularly those with diabetes and hypertension.
• Coronary microvascular dysfunction is a key contributor to HFpEF pathogenesis.
• Endothelial cells (ECs) rely on glycolysis for energy, crucial for angiogenesis, migration, and proliferation.

Purpose of the Study:

• To review the role of Sirtuin 3 (SIRT3) in endothelial cell (EC) metabolic reprogramming.
• To explore the impact of SIRT3 deficiency on EC function and its link to coronary microvascular dysfunction and HFpEF.

Main Methods:

• Literature review focusing on SIRT3 function in ECs.
• Analysis of metabolic pathways (glycolysis vs. oxidative phosphorylation) in ECs.
• Examination of cellular processes including apoptosis, senescence, and intercellular communication.

Main Results:

• SIRT3 deficiency in ECs leads to decreased glycolysis and increased mitochondrial respiration with elevated reactive oxygen species.
• SIRT3 loss promotes EC apoptosis and senescence, evidenced by increased p53 acetylation.
• Impaired SIRT3-mediated EC metabolism disrupts EC/pericyte/cardiomyocyte interactions, causing coronary microvascular rarefaction.

Conclusions:

• SIRT3 plays a critical role in regulating EC metabolism and maintaining vascular homeostasis.
• Dysfunctional SIRT3-mediated EC metabolism contributes to cardiomyocyte hypoxia, stiffness, fibrosis, and ultimately diastolic dysfunction in HFpEF.
• Targeting SIRT3 in ECs may offer a therapeutic strategy for HFpEF.