Interference with PPARγ in endothelium accelerates angiotensin II-induced endothelial dysfunction

Chunyan Hu; Ko-Ting Lu; Masashi Mukohda; Deborah R Davis; Frank M Faraci; Curt D Sigmund

doi:10.1152/physiolgenomics.00087.2015

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Interference with PPARγ in endothelium accelerates angiotensin II-induced endothelial dysfunction

Journal article

Open access

Peer reviewed

Interference with PPARγ in endothelium accelerates angiotensin II-induced endothelial dysfunction

Chunyan Hu, Ko-Ting Lu, Masashi Mukohda, Deborah R Davis, Frank M Faraci and Curt D Sigmund

Physiological genomics, Vol.48(2), pp.124-134

02/2016

DOI: 10.1152/physiolgenomics.00087.2015

PMCID: PMC4729699

PMID: 26534936

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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.

Oxidative Stress

Ligands

Blood Pressure

Reactive Oxygen Species - metabolism

Antioxidants - metabolism

Male

NF-kappa B - metabolism

Acetylcholine - metabolism

PPAR gamma - metabolism

Diet, High-Fat

Superoxides - metabolism

Real-Time Polymerase Chain Reaction

Superoxide Dismutase - metabolism

PPAR gamma - genetics

Heart Rate

Angiotensin II - metabolism

Mice, Inbred C57BL

Spectrometry, Fluorescence

Mice, Transgenic

Catalase - metabolism

Animals

PPAR gamma - antagonists & inhibitors

Endothelium, Vascular - metabolism

Endothelium, Vascular - pathology

Carotid Arteries - pathology

Mice

Details

Title: Subtitle: Interference with PPARγ in endothelium accelerates angiotensin II-induced endothelial dysfunction
Creators: Chunyan Hu - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
Ko-Ting Lu - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
Masashi Mukohda - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
Deborah R Davis - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
Frank M Faraci - 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
Curt D Sigmund - 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
Resource Type: Journal article
Publication Details: Physiological genomics, Vol.48(2), pp.124-134
DOI: 10.1152/physiolgenomics.00087.2015
PMID: 26534936
PMCID: PMC4729699
NLM abbreviation: Physiol Genomics
ISSN: 1094-8341
eISSN: 1531-2267
Publisher: United States
Grant note: R01 HL125603 / NHLBI NIH HHS HL-062984 / NHLBI NIH HHS HL-084207 / NHLBI NIH HHS HL-048058 / NHLBI NIH HHS R01 HL131689 / NHLBI NIH HHS HL-113863 / NHLBI NIH HHS P01 HL062984 / NHLBI NIH HHS HL-125603 / NHLBI NIH HHS
Language: English
Date published: 02/2016
Academic Unit: Molecular Physiology and Biophysics; Pathology; Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040246702771

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