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Arterioscler Thromb Vasc Biol. 2013 Mar;33(3):621-8. doi: 10.1161/ATVBAHA.112.300665. Epub 2013 Jan 17.

Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cells.

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  • 1Department of Pulmonary Immunity, Center for Infection and Immunity of Lille, Inserm U1019, CNRS UMR8204, Université Lille Nord de France, Lille, France.



Dyslipidemia contributes to endothelial dysfunction in type 2 diabetes mellitus. Fenofibrate (FF), a ligand of the peroxisome proliferator-activated receptor-α (PPARα), 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.


FF impaired the capacity of transforming growth factor-β to induce ET-1 gene expression. PPARα activation by FF increased expression of the transcriptional repressor Krüppel-like factor 11 and its binding to the ET-1 gene promoter. Knockdown of Krüppel-like factor 11 expression potentiated basal and transforming growth factor-β-stimulated ET-1 expression, suggesting that Krüppel-like factor 11 downregulates ET-1 expression. FF, in a PPARα-independent manner, and insulin enhanced glycogen synthase kinase-3β 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.


FF decreases ET-1 expression by a PPARα-dependent mechanism, via transcriptional induction of the Krüppel-like factor 11 repressor and by PPARα-independent actions via inhibition of glycogen synthase kinase-3 activity.

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