title: PPARdelta-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis.
abstract: Activation of the nuclear hormone receptor peroxisome proliferator-activated receptor delta (PPARdelta) has been shown to improve insulin resistance, adiposity, and plasma HDL levels. However, its antiatherogenic role remains controversial. Here we report atheroprotective effects of PPARdelta activation in a model of angiotensin II (AngII)-accelerated atherosclerosis, characterized by increased vascular inflammation related to repression of an antiinflammatory corepressor, B cell lymphoma-6 (Bcl-6), and the regulators of G protein-coupled signaling (RGS) proteins RGS4 and RGS5. In this model, administration of the PPARdelta agonist GW0742 (1 or 10 mg/kg) substantially attenuated AngII-accelerated atherosclerosis without altering blood pressure and increased vascular expression of Bcl-6, RGS4, and RGS5, which was associated with suppression of inflammatory and atherogenic gene expression in the artery. In vitro studies demonstrated similar changes in AngII-treated macrophages: PPARdelta activation increased both total and free Bcl-6 levels and inhibited AngII activation of MAP kinases, p38, and ERK1/2. These studies uncover crucial proinflammatory mechanisms of AngII and highlight actions of PPARdelta activation to inhibit AngII signaling, which is atheroprotective.
authors.affiliation: Division of Endocrinology, Diabetes, and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-7073, USA.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Takata
authors.forename: Joey
authors.initials: J
authors.lastname: Liu
authors.forename: Fen
authors.initials: F
authors.lastname: Yin
authors.forename: Alan R
authors.initials: AR
authors.lastname: Collins
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lyon
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Lee
authors.forename: Annette R
authors.initials: AR
authors.lastname: Atkins
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.forename: Grant D
authors.initials: GD
authors.lastname: Barish
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.forename: Willa A
authors.initials: WA
authors.lastname: Hsueh
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Tangirala
mesh_terms: D054392:Adipokines / Q000097:blood; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006937:Hypercholesterolemia / Q000097:blood / Q000473:pathology; D015228:Hypertriglyceridemia / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D047494:PPAR delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000097:blood / Q000494:pharmacology; D014158:Transcription, Genetic / Q000235:genetics; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D054392:Adipokines; D000804:Angiotensin II; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases; D047494:PPAR delta; D051560:Proto-Oncogene Proteins c-bcl-6; D011973:Receptors, LDL; D013844:Thiazoles; 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