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J. Biol. Chem., Vol. 282, Issue 18, 13769-13779, May 4, 2007

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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^¶, and Mukesh K. Jain¹

From the Cardiovascular Research Institute, Case Western Reserve University, Cleveland, Ohio 44106-7290, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School and ^¶Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, ^||Center for Immunology and Inflammatory Diseases and Cardiology Division, Massachusetts General Hospital, Charlestown, Massachusetts 02129, Harvard Medical School, Boston, Massachusetts 02115, and ^**Department of Medicine, Gastroenterology Division, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104

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 Kruppellike factor 4 leads to enhancement of tumor necrosis factor -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.

Received for publication, January 3, 2007 , and in revised form, March 1, 2007.

^* This work was supported by National Institutes of Health Grants HL-69477, HL-72952, HL-75427, and HL-76754 (to M. K. J.) and P01 HL48743 (to M. K. J.), T32 HOLO 760420 (to A. H.), Ruth L. Kirschstein National Research Service Award F32HL078183 (to A. K.), and American Heart Association Postdoctoral Fellowship 0425789T and Scientist Development Grant 0635579T (to Z. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed: Cardiovascular Research Institute, Case Western Reserve University, Wolstein Research Bldg., 2103 Cornell Rd., Cleveland, OH 44106-7290. Tel.: 216-368-3391; Fax: 216-368-0556; E-mail: mukesh.jain2{at}case.edu.

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