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Título

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

Autor Glineur, Corine; Gross, Barbara; Neve, Bernadette; Rommens, Corinne; Chew, Gerard T.; Marin-Nizard, Françoise; Rodríguez-Pascual, Fernando; Lamas Peláez, Santiago ; Watts, Gerard F.; Staels, Bart
Palabras clave Endothelium
Glycogen synthase kinase-3
Peroxisome proliferator–activated receptor-α
Type 2 diabetes mellitus
Endothelin-1
Fecha de publicación 2013
EditorAmerican Heart Association
Citación Arteriosclerosis, Thrombosis, and Vascular Biology 33: 621- 628 (2013)
ResumenObjective-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. Methods and Results-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. Conclusion-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. © 2013 American Heart Association, Inc.
URI http://hdl.handle.net/10261/95891
DOI10.1161/ATVBAHA.112.300665
Identificadoresdoi: 10.1161/ATVBAHA.112.300665
issn: 1079-5642
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