Kruppel-like factor 4 regulates endothelial inflammation

Anne Hamik, Zhiyong Lin, Ajay Kumar, Mercedes Balcells, Sumita Sinha, Jonathan Katz, Mark W. Feinberg, Robert E. Gerszten, Elazer R. Edelman, Mukesh K. Jain

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Resum

The vascular endothelium plays a critical role in vascular homeostasis. Inflammatory cytokines and non-laminar blood flow induce endothelial dysfunction and confer a pro-adhesive and pro-thrombotic phenotype. Therefore, identification of factors that mediate the effects of these stimuli on endothelial function is of considerable interest. Kruppel-like factor 4 expression has been documented in endothelial cells, but a function has not been described. In this communication we describe the expression in vitro and in vivo of Kruppel-like factor 4 in human and mouse endothelial cells. Furthermore, we demonstrate that endothelial Kruppel-like factor 4 is induced by pro-inflammatory stimuli and shear stress. Overexpression of Kruppel-like factor 4 induces expression of multiple anti-inflammatory and anti-thrombotic factors including endothelial nitric-oxide synthase and thrombomodulin, whereas knockdown of Kruppel-like factor 4 leads to enhancement of tumor necrosis factor α-induced vascular cell adhesion molecule-1 and tissue factor expression. The functional importance of Kruppel-like factor 4 is verified by demonstrating that Kruppel-like factor 4 expression markedly decreases inflammatory cell adhesion to the endothelial surface and prolongs clotting time under inflammatory states. Kruppel-like factor 4 differentially regulates the promoter activity of pro- and anti-inflammatory genes in a manner consistent with its anti-inflammatory function. These data implicate Kruppel-like factor 4 as a novel regulator of endothelial activation in response to pro-inflammatory stimuli.

Idioma originalAnglès
Pàgines (de-a)13769-13779
Nombre de pàgines11
RevistaJournal of Biological Chemistry
Volum282
Número18
DOIs
Estat de la publicacióPublicada - 4 de maig 2007
Publicat externament

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