| First Author | Mukohda M | Year | 2016 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 310 |
| Issue | 1 | Pages | H39-48 |
| PubMed ID | 26566726 | Mgi Jnum | J:231346 |
| Mgi Id | MGI:5770214 | Doi | 10.1152/ajpheart.00490.2015 |
| Citation | Mukohda M, et al. (2016) Endothelial PPAR-gamma provides vascular protection from IL-1beta-induced oxidative stress. Am J Physiol Heart Circ Physiol 310(1):H39-48 |
| abstractText | Loss of peroxisome proliferator-activated receptor (PPAR)-gamma function in the vascular endothelium enhances atherosclerosis and NF-kappaB target gene expression in high-fat diet-fed apolipoprotein E-deficient mice. The mechanisms by which endothelial PPAR-gamma regulates inflammatory responses and protects against atherosclerosis remain unclear. To assess functional interactions between PPAR-gamma and inflammation, we used a model of IL-1beta-induced aortic dysfunction in transgenic mice with endothelium-specific overexpression of either wild-type (E-WT) or dominant negative PPAR-gamma (E-V290M). IL-1beta dose dependently decreased IkappaB-alpha, increased phospho-p65, and increased luciferase activity in the aorta of NF-kappaB-LUC transgenic mice. IL-1beta 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-gamma agonist rosiglitazone or in E-WT. Conversely, IL-1beta-induced endothelial dysfunction was worsened in the aorta from E-V290M mice. Although IL-1beta increased the expression of NF-kappaB target genes, NF-kappaB p65 inhibitor did not alleviate endothelial dysfunction induced by IL-1beta. Tempol, a SOD mimetic, partially restored ACh responsiveness in the IL-1beta-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-gamma-mediated protection involves antioxidant effects. IL-1beta 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-gamma but were worsened in the aorta with E-V290M even in the absence of IL-1beta. We conclude that PPAR-gamma protects against IL-1beta-mediated endothelial dysfunction through a reduction of oxidative stress responses but not by blunting IL-1beta-mediated NF-kappaB activity. |
