title: Interference with PPARγ in endothelium accelerates angiotensin II-induced endothelial dysfunction.
abstract: The ligand activated nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) in the endothelium regulates vascular function and blood pressure (BP). We previously reported that transgenic mice (E-V290M) with selectively targeted endothelial-specific expression of dominant negative PPARγ exhibited endothelial dysfunction when treated with a high-fat diet, and exhibited an augmented pressor response to angiotensin II (ANG II). We hypothesize that interference with endothelial PPARγ would exacerbate ANG II-induced endothelial dysfunction. Endothelial function was examined in E-V290M mice infused with a subpressor dose of ANG II (120 ng·kg(-1)·min(-1)) or saline for 2 wk. ANG II infusion significantly impaired the responses to the endothelium-dependent agonist acetylcholine both in basilar and carotid arteries from E-V290M but not NT mice. This impairment was not due to increased BP, which was not significantly different in ANG II-infused E-V290M compared with NT mice. Superoxide levels, and expression of the pro-oxidant Nox2 gene was elevated, whereas expression of the anti-oxidant genes Catalase and SOD3 decreased in carotid arteries from ANG II-infused E-V290M mice. Increased p65 and decreased Iκ-Bα suggesting increased NF-κB activity was also observed in aorta from ANG II-infused E-V290M mice. The responses to acetylcholine were significantly improved both in basilar and carotid arteries after treatment with Tempol (1 mmol/l), a scavenger of superoxide. These findings provide evidence that interference with endothelial PPARγ accelerates ANG II-mediated endothelial dysfunction both in cerebral and conduit arteries through an oxidative stress-dependent mechanism, suggesting a role for endothelial PPARγ in protecting against ANG II-induced endothelial dysfunction.
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa;
authors.forename: Chunyan
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa;
authors.forename: Ko-Ting
authors.initials: KT
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa;
authors.forename: Masashi
authors.initials: M
authors.lastname: Mukohda
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa;
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Davis
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Faraci
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and curt-sigmund@uiowa.edu.
authors.forename: Curt D
authors.identifier: http://orcid.org/0000-0002-1453-0921
authors.initials: CD
authors.lastname: Sigmund
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001794:Blood Pressure; D002339:Carotid Arteries / Q000473:pathology; D002374:Catalase / Q000378:metabolism; D059305:Diet, High-Fat; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D006339:Heart Rate; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013050:Spectrometry, Fluorescence; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D000975:Antioxidants; D008024:Ligands; D016328:NF-kappa B; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D013481:Superoxides; D000804:Angiotensin II; D002374:Catalase; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase; D000109:Acetylcholine
keywords: PPARγ; angiotensin II; endothelial dysfunction; endothelium; oxidative stress