Journal article
Dominant negative PPARγ promotes atherosclerosis, vascular dysfunction, and hypertension through distinct effects in endothelium and vascular muscle
American journal of physiology. Regulatory, integrative and comparative physiology, Vol.304(9), pp.R690-R701
Integrative and Translational Physiology: Inflammation and Immunity in Organ System Physiology
05/01/2013
DOI: 10.1152/ajpregu.00607.2012
PMCID: PMC3652079
PMID: 23447133
Abstract
Agonists of the nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) have potent insulin-sensitizing effects and inhibit atherosclerosis progression in patients with Type II diabetes. Conversely, missense mutations in the ligand-binding domain of PPARγ that render the transcription factor dominant negative (DN) cause early-onset hypertension and Type II diabetes. We tested the hypothesis that DN PPARγ-mediated interference of endogenous wild-type PPARγ in the endothelium and vascular smooth muscle exacerbates atherosclerosis in apolipoprotein E-deficient (ApoE
−/−
) mice. Endothelium-specific expression of DN PPARγ on the ApoE
−/−
background unmasked significant impairment of endothelium-dependent relaxation in aortic rings, increased systolic blood pressure, altered expression of atherogenic markers (e.g.,
Cd36
,
Mcp1
,
Catalase
), and enhanced diet-induced atherosclerotic lesion formation in aorta. Smooth muscle-specific expression of DN PPARγ, which induces aortic dysfunction and increased systolic blood pressure at baseline, also resulted in enhanced diet-induced atherosclerotic lesion formation in aorta on the ApoE
−/−
background that was associated with altered expression of a shared, yet distinct, set of atherogenic markers (e.g.,
Cd36
,
Mcp1
,
Osteopontin
,
Vcam1
). In particular, induction of
Osteopontin
expression by smooth muscle-specific DN PPARγ correlated with increased plaque calcification. These data demonstrate that inhibition of PPARγ function specifically in the vascular endothelium or smooth muscle may contribute to cardiovascular disease.
Details
- Title: Subtitle
- Dominant negative PPARγ promotes atherosclerosis, vascular dysfunction, and hypertension through distinct effects in endothelium and vascular muscle
- Creators
- Christopher J Pelham - Departments ofHenry L Keen - Pharmacology andSteven R Lentz - Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IowaCurt D Sigmund - Departments of
- Resource Type
- Journal article
- Publication Details
- American journal of physiology. Regulatory, integrative and comparative physiology, Vol.304(9), pp.R690-R701
- Series
- Integrative and Translational Physiology: Inflammation and Immunity in Organ System Physiology
- DOI
- 10.1152/ajpregu.00607.2012
- PMID
- 23447133
- PMCID
- PMC3652079
- NLM abbreviation
- Am J Physiol Regul Integr Comp Physiol
- ISSN
- 0363-6119
- eISSN
- 1522-1490
- Publisher
- American Physiological Society
- Grant note
- HL-084207; HL-048058; HL-061446; HL-062984; NS-024621; HL-063943; HL-062984; NS-024621 / National Institutes of Health
- Language
- English
- Date published
- 05/01/2013
- Academic Unit
- Molecular Physiology and Biophysics; Hematology, Oncology, and Blood & Marrow Transplantation; Neuroscience and Pharmacology; Internal Medicine; Iowa Institute of Human Genetics
- Record Identifier
- 9984094530402771
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