title: Dominant negative PPARγ promotes atherosclerosis, vascular dysfunction, and hypertension through distinct effects in endothelium and vascular muscle.
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.
authors: Departments of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors: Christopher J
authors: CJ
authors: Pelham
authors: Henry L
authors: HL
authors: Keen
authors: Steven R
authors: SR
authors: Lentz
authors: Curt D
authors: CD
authors: Sigmund
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology / Q000503:physiopathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000503:physiopathology*; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D004032:Diet; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005799:Genes, Dominant / Q000235:genetics / Q000502:physiology; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D009213:Myography; D009599:Nitroprusside / Q000494:pharmacology; D047495:PPAR gamma / Q000235:genetics* / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D014652:Vascular Diseases / Q000235:genetics* / Q000503:physiopathology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D047495:PPAR gamma; D014665:Vasodilator Agents; D009599:Nitroprusside; D000109:Acetylcholine
keywords: PPARγ; atherosclerosis; endothelium; smooth muscle