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23447133
Dominant negative PPARγ promotes atherosclerosis, vascular dysfunction, and hypertension through distinct effects in endothelium and vascular muscle.

Am J Physiol Regul Integr Comp Physiol, 2013/5/01;304(9):R690-701.

Pelham CJ[1], Keen HL, Lentz SR, Sigmund CD

Affiliations

PMID: 23447133DOI: 10.1152/ajpregu.00607.2012

Impact factor: 3.21

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.

Keywords: PPARγ; atherosclerosis; endothelium; smooth muscle

MeSH terms
Acetylcholine; Animals; Aorta, Thoracic; Apolipoproteins E; Atherosclerosis; Blood Pressure; Diet; Disease Progression; Endothelium, Vascular; Genes, Dominant; Hypertension; Mice; Mice, Knockout; Mice, Transgenic; Muscle, Smooth, Vascular; Myography; Nitroprusside; PPAR gamma; Real-Time Polymerase Chain Reaction; Vascular Diseases; Vasodilator Agents
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