title: Role of UCP2 in the protective effects of PPARβ/δ activation on lipopolysaccharide-induced endothelial dysfunction.
abstract: Bacterial endotoxin lipopolysaccharide (LPS) activates inflammatory pathways, induces cytokine expression in the endothelium, augments reactive oxygen species (ROS) production in the vascular wall, and induces endothelial dysfunction. The aim of the present study was to analyze the effects of peroxisome proliferator-activated receptor (PPAR)β/δ activation on LPS-induced inflammation, oxidative stress and endothelial dysfunction and to determine whether uncoupling protein-2 (UCP2) plays a role in these effects. In vivo, the PPARβ/δ agonist GW0742 treatment prevented the LPS-induced reduction in aortic relaxation, the increase in vascular ROS production, the upregulation of NOX1, NOX2, p47(phox), and p22(phox) mRNA levels, and the endoplasmic reticulum (ER) stress markers in mice. We show that in mouse aortic endothelial cells (MAECs), GW0742 prevented the decreased A23187-stimulated nitric oxide (NO) production, and the increased intracellular ROS levels caused by exposure to LPS in vitro. The PPARβ/δ antagonist GSK0660 abolished all these in vivo and in vitro protective effects induced by GW0742. This agonist also restored the reduced expression of UCP2 and mitofusin-2 induced by LPS. The effects of GW0742 on NO and ROS production in MAEC exposed to LPS were abolished by the UCP2 inhibitor genipin or by siRNA targeting UCP-2. Genipin also suppressed the expressional changes on NADPH oxidase and ER stress markers induced by GW0742. In conclusion, PPARβ/δ activation restored the LPS-induced endothelial dysfunction by upregulation of UCP2, with the subsequent alleviation of ER stress and NADPH oxidase activity, thus reducing intracellular ROS production and increasing NO bioavailability.
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, ibs.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, ibs.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.
authors.forename: Iñaki
authors.initials: I
authors.lastname: Robles-Vera
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Tamargo
authors.affiliation: INSERM U1063, Sopam, Angers University, F-49045 Angers, France.
authors.forename: María Carmen
authors.initials: MC
authors.lastname: Martínez
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain; CIBER de Enfermedades Respiratorias, CIBERES, 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, ibs.GRANADA, Granada, Spain. Electronic address: jmduarte@ugr.es.
authors.forename: Juan
authors.initials: J
authors.lastname: Duarte
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D003573:Cytochrome b Group / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048068:PPAR-beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D046509:Tissue Culture Techniques; D000071246:Uncoupling Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D000001:Calcimycin; D003573:Cytochrome b Group; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D009569:Nitric Oxide; D047495:PPAR gamma; D048068:PPAR-beta; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013450:Sulfones; D013844:Thiazoles; D013876:Thiophenes; D000071246:Uncoupling Protein 2; C529769:GSK0660; C000604390:Ucp2 protein, mouse; 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; C488842:Cybb protein, mouse; C000614711:NOX1 protein, mouse; C515614:Cyba protein, mouse; C060505:neutrophil cytosolic factor 1
keywords: ER stress; Endothelial dysfunction; NADPH oxidase; Oxidative stress; PPARβ/δ; UCP2