Fenofibrate Inhibits Endothelin-1 Expression by Peroxisome Proliferator-Activated Receptor α-Dependent and Independent Mechanisms in Human Endothelial Cells

Objective-Dyslipidemia contributes to endothelial dysfunction in type 2 diabetes mellitus. Fenofibrate (FF), a ligand of the peroxisome proliferator-activated receptor-alpha (PPAR alpha), has beneficial effects on microvascular complications. FF may act on the endothelium by regulating vasoactive factors, including endothelin-1 (ET-1). In vitro, FF decreases ET-1 expression in human microvascular endothelial cells. We investigated the molecular mechanisms involved in the effect of FF treatment on plasma levels of ET-1 in type 2 diabetes mellitus patients. Methods and Results-FF impaired the capacity of transforming growth factor-beta to induce ET-1 gene expression. PPAR alpha activation by FF increased expression of the transcriptional repressor Kruppel-like factor 11 and its binding to the ET-1 gene promoter. Knockdown of Kruppel-like factor 11 expression potentiated basal and transforming growth factor-beta-stimulated ET-1 expression, suggesting that Kruppel-like factor 11 downregulates ET-1 expression. FF, in a PPAR alpha-independent manner, and insulin enhanced glycogen synthase kinase-3 beta phosphorylation thus reducing glycogen synthase kinase-3 activity that contributes to the FF-mediated reduction of ET-1 gene expression. In type 2 diabetes mellitus, improvement of flow-mediated dilatation of the brachial artery by FF was associated with a decrease in plasma ET-1. Conclusion-FF decreases ET-1 expression by a PPAR alpha-dependent mechanism, via transcriptional induction of the Kruppel-like factor 11 repressor and by PPAR alpha-independent actions via inhibition of glycogen synthase kinase-3 activity. (Arterioscler Thromb Vasc Biol. 2013;33:621-628.)