Document Detail

PPARdelta-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis.
MedLine Citation:
PMID:  18337495     Owner:  NLM     Status:  MEDLINE    
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.
Yasunori Takata; Joey Liu; Fen Yin; Alan R Collins; Christopher J Lyon; Chih-Hao Lee; Annette R Atkins; Michael Downes; Grant D Barish; Ronald M Evans; Willa A Hsueh; Rajendra K Tangirala
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-03-12
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  105     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-19     Completed Date:  2008-04-15     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4277-82     Citation Subset:  IM    
Division of Endocrinology, Diabetes, and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-7073, USA.
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MeSH Terms
Adipokines / blood
Angiotensin II / pharmacology*
Atherosclerosis / genetics,  metabolism*,  pathology
Cell Movement / drug effects
Enzyme Activation / drug effects
Gene Expression Regulation / drug effects
Hypercholesterolemia / blood,  pathology
Hypertriglyceridemia / metabolism,  pathology
Inflammation / genetics,  metabolism,  pathology
Macrophages / cytology,  drug effects,  metabolism
Mice, Knockout
Mitogen-Activated Protein Kinases / metabolism
PPAR delta / antagonists & inhibitors,  metabolism*
Proto-Oncogene Proteins c-bcl-6 / genetics,  metabolism
Receptors, LDL / deficiency,  genetics,  metabolism
Signal Transduction / drug effects
Thiazoles / blood,  pharmacology
Transcription, Genetic / genetics
Grant Support
P01 HL088093/HL/NHLBI NIH HHS; R01 HL105278/HL/NHLBI NIH HHS; R37 DK057978/DK/NIDDK NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
0/Adipokines; 0/GW0742; 0/Ligands; 0/PPAR delta; 0/Proto-Oncogene Proteins c-bcl-6; 0/Receptors, LDL; 0/Thiazoles; 11128-99-7/Angiotensin II; EC Protein Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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