FUNDC1 down-regulation reduces mitophagy and contributes to aging vascular endothelial dysfunction

AIM To investigate the role of FUNDC1-mediated mitophagy in coronary vascular aging.

METHODS Aged mice (18 months) and young mice (8 weeks) were used to explore the relationship between age and coronary endothelial function. Primary cardiac microvascular endothelial cells (CMECs) from mouse myocardial tissue were isolated and cultured, and the aging model was constructed by 40 passages. Mitophagy levels in CMECs were measured using mt-Keima 543/458 nm fluorescence, and mitochondrial ROS levels and membrane potential were measured using MitoSOX and JC-1. Endothelial-specific FUNDC1 knockout (Fundc1fl/Y/Tek-Cre) mice were constructed and endothelial-specific over-expression of FUNDC1 was performed using adeno-associated virus to verify the key role of FUNDC1 in endothelial dysfunction caused by aging.

RESULTS The coronary arteries of aged mice showed diastolic dysfunction and decreased FUNDC1 expression in endothelial cells (P<0.01). Aging led to impaired mitophagy, abnormal mitochondrial membrane potential and ROS accumulation in CMECs. Deletion of endothelium-specific FUNDC1 resulted in decreased coronary artery function and increased senescence-associated β-galactosidase (SA-β-gal) positive staining in mice. FUNDC1 over-expression improved aging-induced coronary endothelial function and reduced SA-β-gal positive staining.

CONCLUSION Down-regulation of FUNDC1-mediated mitochondrial autophagy is one of the important causes of aging coronary endothelial dysfunction, and this study provides new ideas and targets for alleviating vascular endothelial aging.