Role of endothelial PPARγ: Protection against vascular dysfunction induced by IL‐1β

Abstract

Peroxisome proliferator‐activated receptor gamma (PPARγ) has been proposed to mediate anti‐inflammatory actions by promoting the degradation of the p65 subunit of nuclear factor kappa B (NFκB). We hypothesize that PPARγ protects against NFκB‐induced vascular dysfunction by promoting p65 degradation in vascular endothelial cells (EC). We used a model of interleukin‐1β (IL‐1β)‐induced aortic dysfunction. Aorta was treated with IL‐1β (24 hr) in vitro and then EC function was measured in an organ chamber. IL‐1β dose‐dependently decreased IκBα expression, increased phospho‐p65, and increased luciferase activity in NFκB‐Luc transgenic mice. IL‐1β dose‐dependently reduced EC‐dependent relaxation by acetylcholine (ACh). The loss of ACh responsiveness was partially improved by pretreating vessels with the PPARγ agonist, rosiglitazone, or in transgenic mice over‐expressing wildtype PPARγ specifically in EC (E‐WT). Consistent with this, low dose IL‐1β was sufficient to cause EC dysfunction in aorta from transgenic mice expressing dominant negative PPARγ specifically in EC (E‐V290M). A p65 inhibitor peptide did not alleviate EC dysfunction induced by IL‐1β, but Tempol, a superoxide dismutase mimetic partially restored ACh responsiveness in both control and E‐WT aorta treated with IL‐1β. TUDCA, a chemical chaperone which reduces endoplasmic reticulum (ER) stress significantly improved EC dysfunction induced by IL‐1β in control aorta, but not aorta from E‐WT mice. Aorta isolated from CHOP‐deficient mice exhibited less IL‐1β‐induced EC dysfunction than control mice. These data suggest that EC PPARγ protects against IL‐1β‐mediated EC dysfunction, possibly through the reduction of reactive oxygen species and blunting IL‐1β‐mediated ER stress.