Endothelial PPAR-γ provides vascular protection from IL-1β-induced oxidative stress

Masashi Mukohda; Madeliene Stump; Pimonrat Ketsawatsomkron; Chunyan Hu; Frederick W Quelle; Curt D Sigmund

doi:10.1152/ajpheart.00490.2015

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Endothelial PPAR-γ provides vascular protection from IL-1β-induced oxidative stress

Journal article

Open access

Peer reviewed

Endothelial PPAR-γ provides vascular protection from IL-1β-induced oxidative stress

Masashi Mukohda, Madeliene Stump, Pimonrat Ketsawatsomkron, Chunyan Hu, Frederick W Quelle and Curt D Sigmund

American journal of physiology. Heart and circulatory physiology, Vol.310(1), pp.H39-H48

01/01/2016

DOI: 10.1152/ajpheart.00490.2015

PMCID: PMC4796462

PMID: 26566726

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Abstract

Loss of peroxisome proliferator-activated receptor (PPAR)-γ function in the vascular endothelium enhances atherosclerosis and NF-κB target gene expression in high-fat diet-fed apolipoprotein E-deficient mice. The mechanisms by which endothelial PPAR-γ regulates inflammatory responses and protects against atherosclerosis remain unclear. To assess functional interactions between PPAR-γ and inflammation, we used a model of IL-1β-induced aortic dysfunction in transgenic mice with endothelium-specific overexpression of either wild-type (E-WT) or dominant negative PPAR-γ (E-V290M). IL-1β dose dependently decreased IκB-α, increased phospho-p65, and increased luciferase activity in the aorta of NF-κB-LUC transgenic mice. IL-1β also dose dependently reduced endothelial-dependent relaxation by ACh. The loss of ACh responsiveness was partially improved by pretreatment of the vessels with the PPAR-γ agonist rosiglitazone or in E-WT. Conversely, IL-1β-induced endothelial dysfunction was worsened in the aorta from E-V290M mice. Although IL-1β increased the expression of NF-κB target genes, NF-κB p65 inhibitor did not alleviate endothelial dysfunction induced by IL-1β. Tempol, a SOD mimetic, partially restored ACh responsiveness in the IL-1β-treated aorta. Notably, tempol only modestly improved protection in the E-WT aorta but had an increased protective effect in the E-V290M aorta compared with the aorta from nontransgenic mice, suggesting that PPAR-γ-mediated protection involves antioxidant effects. IL-1β increased ROS and decreased the phospho-endothelial nitric oxide synthase (Ser(1177))-to-endothelial nitric oxide synthase ratio in the nontransgenic aorta. These effects were completely abolished in the aorta with endothelial overexpression of WT PPAR-γ but were worsened in the aorta with E-V290M even in the absence of IL-1β. We conclude that PPAR-γ protects against IL-1β-mediated endothelial dysfunction through a reduction of oxidative stress responses but not by blunting IL-1β-mediated NF-κB activity.

Interleukin-1beta - pharmacology

Phosphorylation

Reactive Oxygen Species - metabolism

Humans

Endothelium, Vascular - drug effects

Male

Aorta - metabolism

I-kappa B Proteins - metabolism

PPAR gamma - metabolism

Aortic Diseases - metabolism

Dose-Response Relationship, Drug

Inflammation Mediators - metabolism

Aortic Diseases - prevention & control

Female

Aorta - physiopathology

Nitric Oxide Synthase Type III - metabolism

Aortic Diseases - pathology

PPAR gamma - genetics

NF-KappaB Inhibitor alpha

Vasodilator Agents - pharmacology

Endothelial Cells - metabolism

Aorta - drug effects

Mice, Inbred C57BL

Endothelium, Vascular - physiopathology

Gene Expression Regulation

Genotype

Mice, Transgenic

Antioxidants - pharmacology

Aorta - pathology

Aortic Diseases - physiopathology

Phenotype

Animals

Signal Transduction - drug effects

Transcription Factor RelA - metabolism

Endothelium, Vascular - metabolism

PPAR gamma - agonists

Endothelium, Vascular - pathology

Oxidative Stress - drug effects

Vasodilation - drug effects

Endothelial Cells - pathology

Endothelial Cells - drug effects

Details

Title: Subtitle: Endothelial PPAR-γ provides vascular protection from IL-1β-induced oxidative stress
Creators: Masashi Mukohda - Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
Madeliene Stump - Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
Pimonrat Ketsawatsomkron - Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
Chunyan Hu - Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
Frederick W Quelle - Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
Curt D Sigmund - Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa curt-sigmund@uiowa.edu
Resource Type: Journal article
Publication Details: American journal of physiology. Heart and circulatory physiology, Vol.310(1), pp.H39-H48
Publisher: United States
DOI: 10.1152/ajpheart.00490.2015
PMID: 26566726
PMCID: PMC4796462
ISSN: 0363-6135
eISSN: 1522-1539
Grant note: R01 HL125603 / NHLBI NIH HHS HL-062984 / NHLBI NIH HHS HL-084207 / NHLBI NIH HHS HL-048058 / NHLBI NIH HHS T32 GM007337 / NIGMS NIH HHS P01 HL062984 / NHLBI NIH HHS HL-125603 / NHLBI NIH HHS
Language: English
Date published: 01/01/2016
Academic Unit: Molecular Physiology and Biophysics; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040286402771

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