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¹ Cardiovascular Division and Center for Excellence in Vascular Biology, Department of Pathology, ² Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115

Address correspondence to Mukesh K. Jain, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115. Phone: (617) 278-0175; Fax: (617) 732-5132; email: mjain{at}rics.bwh.harvard.edu

The vascular endothelium is a critical regulator of vascular function. Diverse stimuli such as proinflammatory cytokines and hemodynamic forces modulate endothelial phenotype and thereby impact on the development of vascular disease states. Therefore, identification of the regulatory factors that mediate the effects of these stimuli on endothelial function is of considerable interest. Transcriptional profiling studies identified the Kruppel-like factor (KLF)2 as being inhibited by the inflammatory cytokine interleukin-1ß and induced by laminar shear stress in cultured human umbilical vein endothelial cells. Overexpression of KLF2 in umbilical vein endothelial cells robustly induced endothelial nitric oxide synthase expression and total enzymatic activity. In addition, KLF2 overexpression potently inhibited the induction of vascular cell adhesion molecule-1 and endothelial adhesion molecule E-selectin in response to various proinflammatory cytokines. Consistent with these observations, in vitro flow assays demonstrate that T cell attachment and rolling are markedly attenuated in endothelial monolayers transduced with KLF2. Finally, our studies implicate recruitment by KLF2 of the transcriptional coactivator cyclic AMP response element–binding protein (CBP/p300) as a unifying mechanism for these various effects. These data implicate KLF2 as a novel regulator of endothelial activation in response to proinflammatory stimuli.

Key Words: cytokine • endothelium • adhesion • nitric oxide • transcription

Abbreviations used in this paper: BAEC, bovine aortic endothelial cell; eNOS, endothelial nitric oxide synthase; GFP, green fluorescence protein; GST, glutathione S-transferase; HUVEC, umbilical vein endothelial cell; ICAM, intercullular cell adhesion molecule; KLF, Kruppel-like factor; LSS, laminar shear stress; NF-B, nuclear factor B; NO, nitric oxide; VCAM, vascular cell adhesion molecule.

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