Carnitine palmitoyltransferase-1 up-regulation by PPAR-beta/delta prevents lipid-induced endothelial dysfunction

摘要

Fatty acids cause endothelial dysfunction involving increased ROS (reactive oxygen species) and reduced NO (nitric oxide) bioavailability. We show that in MAECs (mouse aortic endothelial cells), the PPAR beta/delta (peroxisome-proliferator-activated receptor beta/delta) agonist GW0742 prevented the decreased A23187-stimulated NO production, phosphorylation of eNOS (endothelial nitric oxide synthase) at Ser(1177) and increased intracellular ROS levels caused by exposure to palmitate in vitro. The impaired endothelium-dependent relaxation to acetylcholine in mouse aorta induced by palmitate was restored by GW0742. In vivo, GW0742 treatment prevented the reduced aortic relaxation, phosphorylation of eNOS at Ser(1177), and increased ROS production and NADPH oxidase in mice fed on a high-fat diet. The PPAR beta/delta antagonist GSK0660 abolished all of these protective effects induced by GW0742. This agonist enhanced the expression of CPT (carnitine palmitoyltransferase)-1. The effects of GW0742 on acetylcholine-induced relaxation in aorta and on NO and ROS production in MAECs exposed to palmitate were abolished by the CPT-1 inhibitor etomoxir or by siRNA targeting CPT-1. GW0742 also inhibited the increase in DAG (diacylglycerol), PKC alpha/beta II (protein kinase C alpha/beta II) activation, and phosphorylation of eNOS at Thr(495) induced by palmitate in MAECs, which were abolished by etomoxir. In conclusion, PPAR beta/delta activation restored the lipid-induced endothelial dysfunction by up-regulation of CPT-1, thus reducing DAG accumulation and the subsequent PKC-mediated ROS production and eNOS inhibition.