Bioinformatic analysis of gene sets regulated by ligand-activated and dominant-negative peroxisome proliferator-activated receptor gamma in mouse aorta

Henry L Keen; Carmen M Halabi; Andreas M Beyer; Willem J de Lange; Xuebo Liu; Nobuyo Maeda; Frank M Faraci; Thomas L Casavant; Curt D Sigmund

doi:10.1161/ATVBAHA.109.200733

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Bioinformatic analysis of gene sets regulated by ligand-activated and dominant-negative peroxisome proliferator-activated receptor gamma in mouse aorta

Journal article

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Bioinformatic analysis of gene sets regulated by ligand-activated and dominant-negative peroxisome proliferator-activated receptor gamma in mouse aorta

Henry L Keen, Carmen M Halabi, Andreas M Beyer, Willem J de Lange, Xuebo Liu, Nobuyo Maeda, Frank M Faraci, Thomas L Casavant and Curt D Sigmund

Arteriosclerosis, thrombosis, and vascular biology, Vol.30(3), pp.518-525

03/2010

DOI: 10.1161/ATVBAHA.109.200733

PMCID: PMC2850258

PMID: 20018933

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Abstract

Drugs that activate peroxisome proliferator-activated receptor (PPAR) gamma improve glucose sensitivity and lower blood pressure, whereas dominant-negative mutations in PPARgamma cause severe insulin resistance and hypertension. We hypothesize that these PPARgamma mutants regulate target genes opposite to those of ligand-mediated activation, and we tested this hypothesis on a genomewide scale. We integrated gene expression data in aorta specimens from mice treated with the PPARgamma ligand rosiglitazone with data from mice containing a globally expressed knockin of the PPARgamma P465L dominant-negative mutation. We also integrated our data with publicly available data sets containing the following: (1) gene expression profiles in many human tissues, (2) PPARgamma target genes in 3T3-L1 adipocytes, and (3) experimentally validated PPARgamma binding sites throughout the genome. Many classic PPARgamma target genes were induced by rosiglitazone and repressed by dominant-negative PPARgamma. A similar pattern was observed for about 90% of the gene sets regulated by both rosiglitazone and dominant-negative PPARgamma. Genes exhibiting this pattern of contrasting regulation were significantly enriched for nearby PPARgamma binding sites. These results provide convincing evidence that the PPARgamma P465L mutation causes transcriptional effects that are opposite to those mediated by PPARgamma ligand, thus validating mice carrying the mutation as a model of PPARgamma interference.

Mice, Inbred C57BL

Computational Biology

Aorta, Thoracic - metabolism

Gene Expression Profiling

PPAR gamma - metabolism

Up-Regulation - drug effects

Animals

Ligands

Models, Animal

Signal Transduction - physiology

Mice

Mutation

Thiazolidinediones - pharmacology

PPAR gamma - genetics

Details

Title: Subtitle: Bioinformatic analysis of gene sets regulated by ligand-activated and dominant-negative peroxisome proliferator-activated receptor gamma in mouse aorta
Creators: Henry L Keen - Department of Internal Medicine and Department of Molecular Physiology and Biophysics, 3181B Medical Education and Biomedical Research Facility, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Carmen M Halabi
Andreas M Beyer
Willem J de Lange
Xuebo Liu
Nobuyo Maeda
Frank M Faraci
Thomas L Casavant
Curt D Sigmund
Resource Type: Journal article
Publication Details: Arteriosclerosis, thrombosis, and vascular biology, Vol.30(3), pp.518-525
DOI: 10.1161/ATVBAHA.109.200733
PMID: 20018933
PMCID: PMC2850258
NLM abbreviation: Arterioscler Thromb Vasc Biol
ISSN: 1079-5642
eISSN: 1524-4636
Publisher: United States
Grant note: T32 GM008629 / NIGMS NIH HHS P01 NS024621-129004 / NINDS NIH HHS P01 NS024621-21A19007 / NINDS NIH HHS R01 HL061446 / NHLBI NIH HHS R01 HL061446-11 / NHLBI NIH HHS T32 GM007337 / NIGMS NIH HHS P01 NS024621-159004 / NINDS NIH HHS R37 HL048058-15 / NHLBI NIH HHS P01 HL084207-01A10001 / NHLBI NIH HHS P01 HL084207-03 / NHLBI NIH HHS P01 NS024621-21A1 / NINDS NIH HHS R37 HL048058-16 / NHLBI NIH HHS P01 NS024621-14 / NINDS NIH HHS P01 NS024621 / NINDS NIH HHS P01 HL062984-080005 / NHLBI NIH HHS P01 NS024621-18 / NINDS NIH HHS P01 HL084207-01A1 / NHLBI NIH HHS R01 HL077145 / NHLBI NIH HHS P01 HL084207 / NHLBI NIH HHS P01 HL084207-030001 / NHLBI NIH HHS P01 NS024621-149004 / NINDS NIH HHS P01 NS024621-160017 / NINDS NIH HHS P01 NS024621-169004 / NINDS NIH HHS HL084207 / NHLBI NIH HHS P01 NS024621-20 / NINDS NIH HHS P01 NS024621-15 / NINDS NIH HHS P01 HL062984-06A10005 / NHLBI NIH HHS P01 NS024621-119004 / NINDS NIH HHS P01 HL062984 / NHLBI NIH HHS P01 NS024621-17 / NINDS NIH HHS R37 HL048058 / NHLBI NIH HHS R01 HL061446-10 / NHLBI NIH HHS R37 HL042630 / NHLBI NIH HHS P01 HL084207-02 / NHLBI NIH HHS HL042630 / NHLBI NIH HHS P01 HL084207-020001 / NHLBI NIH HHS P01 HL062984-070005 / NHLBI NIH HHS P01 NS024621-229007 / NINDS NIH HHS R01 HL061446-09 / NHLBI NIH HHS NS024621 / NINDS NIH HHS R37 HL048058-17 / NHLBI NIH HHS P01 NS024621-19 / NINDS NIH HHS P01 NS024621-13 / NINDS NIH HHS P01 NS024621-139004 / NINDS NIH HHS P01 HL062984-090005 / NHLBI NIH HHS HL062984 / NHLBI NIH HHS P01 NS024621-16 / NINDS NIH HHS
Language: English
Date published: 03/2010
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Molecular Physiology and Biophysics; Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine; Iowa Institute of Human Genetics
Record Identifier: 9984040013402771

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