Aims: Central obesity is associated with increased cardiovascular morbidity and mortality. It has been proposed that increased lipid accumulation in vascular tissue and the consequent increase in oxidative stress may be a missing link between obesity and atherosclerosis. The peroxisome proliferators-activated receptor (PPAR)-γ coactivator 1-α (PGC-1α) is a transcriptional coactivator playing an important role in energy metabolism. PGC-1α is present in vascular cells, but its role in vascular endothelial cells has not been established. In this study, we examined the effect of adenoviral overexpression of PGC-1α (Ad-PGC-1α) in human aortic endothelial cells (HAECs) on apoptosis induced by linoleic acid (LA).
Methods: Effect of PGC-1 on HAECs apoptosis was evaluated by ELISA, WST-1 assay, and caspase activity. Using Ad-PGC-1 and ANT-1 siRNA, effect of PGC-1 and ANT-1 on reactive oxygen species (ROS) production, fatty acid oxidation (FAO) and mitochondrial membrane potential (Δψm) were analyzed.
Results: PGC-1α prevented LA-induced endothelial apoptosis. PGC-1α also reduced LA-induced increases of antioxidant enzyme expression and ROS accumulation at basal state. LA decreased the activity of adenosine nucleotide translocase (ANT), and increased Δψm. In the Ad-PGC-1α-infected HAECs, activity and the mRNA expression of ANT-1 were increased and LA did not increase Δψm. siRNA against ANT-1 reversed the changes induced by PGC-1α.
Conclusion: These data suggest that PGC-1α functions as a physiologic regulator of ROS generation in endothelial cells and that part of this effect is mediated by ANT-dependent increase in FAO.