title: Carnitine palmitoyltransferase-1 up-regulation by PPAR-β/δ prevents lipid-induced endothelial dysfunction.
abstract: 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 PPARβ/δ (peroxisome- proliferator-activated receptor β/δ) agonist GW0742 prevented the decreased A23187-stimulated NO production, phosphorylation of eNOS (endothelial nitric oxide synthase) at Ser1177 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 Ser1177, and increased ROS production and NADPH oxidase in mice fed on a high-fat diet. The PPARβ/δ 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), PKCα/βII (protein kinase Cα/βII) activation, and phosphorylation of eNOS at Thr495 induced by palmitate in MAECs, which were abolished by etomoxir. In conclusion, PPARβ/δ 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.
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Toral
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain Instituto de Investigación Biosanitaria de Granada, Granada, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Romero
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain Instituto de Investigación Biosanitaria de Granada, Granada, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Jiménez
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, 62511 Beni-Suef, Egypt.
authors.forename: Ayman Moawad
authors.initials: AM
authors.lastname: Mahmoud
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, E-08028 Barcelona, Spain.
authors.forename: Emma
authors.initials: E
authors.lastname: Barroso
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Gómez-Guzmán
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Ciber Enfermedades Respiratorias (Ciberes), 28040 Madrid, Spain Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Cogolludo
authors.affiliation: Department of Pharmacology, University Autónoma of Madrid, 28029 Madrid, Spain.
authors.forename: Ana B
authors.initials: AB
authors.lastname: García-Redondo
authors.affiliation: Department of Pharmacology, University Autónoma of Madrid, 28029 Madrid, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Briones
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, E-08028 Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Vázquez-Carrera
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Ciber Enfermedades Respiratorias (Ciberes), 28040 Madrid, Spain Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Pérez-Vizcaíno
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain Instituto de Investigación Biosanitaria de Granada, Granada, Spain jmduarte@ugr.es.
authors.forename: Juan
authors.initials: J
authors.lastname: Duarte
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D000001:Calcimycin / Q000494:pharmacology; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004075:Diglycerides / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects; D008055:Lipids / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048068:PPAR-beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010169:Palmitic Acids / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051571:Protein Kinase C-alpha / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D015854:Up-Regulation; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D000001:Calcimycin; D002334:Carnitine O-Palmitoyltransferase; D004075:Diglycerides; D008055:Lipids; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D047494:PPAR delta; D048068:PPAR-beta; D010169:Palmitic Acids; D051571:Protein Kinase C-alpha; D017382:Reactive Oxygen Species; D013450:Sulfones; D013844:Thiazoles; D013876:Thiophenes; C529769:GSK0660; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds
keywords: CPT-1; NADPH oxidase; PPARβ/δ.; endothelial dysfunction; lipids; mitochondrial ROS