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J. Biol. Chem., Vol. 280, Issue 24, 23371-23379, June 17, 2005

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Induction of KLF2 by Fluid Shear Stress Requires a Novel Promoter Element Activated by a Phosphatidylinositol 3-Kinase-dependent Chromatin-remodeling Pathway^*

Justin P. Huddleson, Nisar Ahmad, Seetha Srinivasan, and Jerry B Lingrel

From the Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

Fluid shear stress maintains vascular homeostasis by influencing endothelial gene expression. One mechanism by which shear stress achieves this is through the induction of transcription factors including Krüppel-like factor 2(KLF2). We have previously reported that a 62-bp region of the KLF2 promoter is responsible for its shear stress-induced expression via the binding of nuclear factors. In this study, we find that the 62-bp shear stress response region contains a 30-bp tripartite palindrome motif. Electrophoretic mobility supershift and chromatin immunoprecipitation assays demonstrate that PCAF (P-300/cAMP-response element-binding protein-binding protein-associated factor)) and heterogeneous nuclear ribonucleoprotein D bind this region as components of the shear stress regulatory complex. We have also characterized a PI3K-dependent/Akt-independent pathway responsible for shear stress-induced KLF2 nuclear binding, promoter activation, and mRNA expression. Furthermore, the shear stress response region of the KLF2 promoter was specifically immunoprecipitated by antibodies against acetylated histones H3 and H4 in shear-stressed but not static hemangioendothelioma cells. The acetylation of these histones was blocked by PI3K inhibition. Finally, we have found that KLF2 increases endothelial nitric-oxide synthase expression in murine endothelial cultures, an effect that is also blocked by PI3K inhibition. These results define the DNA regulatory element, signal transduction pathway, and molecular mechanism activating the flow-dependent expression of a vital endothelial transcription factor.

Received for publication, December 8, 2004 , and in revised form, March 25, 2005.

^* This work was supported by National Institutes of Health Grant R01 HL57281. 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed: University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267-0524. Tel.: 513-558-5324; Fax: 513-558-1190; E-mail: jerrylingrel{at}uc.edu.

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