Endothelial PPAR-γ provides vascular protection from IL-1β-induced oxidative stress. Am J Physiol Heart Circ Physiol 2016 Jan 01;310(1):H39-48
Date
11/15/2015Pubmed ID
26566726Pubmed Central ID
PMC4796462DOI
10.1152/ajpheart.00490.2015Scopus ID
2-s2.0-84953330749 (requires institutional sign-in at Scopus site) 45 CitationsAbstract
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.
Author List
Mukohda M, Stump M, Ketsawatsomkron P, Hu C, Quelle FW, Sigmund CDAuthor
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntioxidants
Aorta
Aortic Diseases
Dose-Response Relationship, Drug
Endothelial Cells
Endothelium, Vascular
Female
Gene Expression Regulation
Genotype
Humans
I-kappa B Proteins
Inflammation Mediators
Interleukin-1beta
Male
Mice, Inbred C57BL
Mice, Transgenic
NF-KappaB Inhibitor alpha
Nitric Oxide Synthase Type III
Oxidative Stress
PPAR gamma
Phenotype
Phosphorylation
Reactive Oxygen Species
Signal Transduction
Transcription Factor RelA
Vasodilation
Vasodilator Agents
