Published online before print February 17, 2005, doi: 10.1161/01.RES.0000159707.05637.a1
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Submitted on December 17, 2004
Revised on January 18, 2005
Accepted on February 7, 2005
Kruppel-Like Factor 2 (KLF2) Regulates Endothelial Thrombotic Function
Zhiyong Lin ;
From the Program in Cardiovascular Transcriptional Biology (Z.L., A.K., S.S., M.K.J.), Cardiovascular Division; Center for Excellence in Vascular Biology (K.P., M.A.G.Jr., G.G.-C.), Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Vanderbilt University Medical Center (D.E.V.), Nashville, Tenn; and Department of Biomedical Engineering (V.B.), Illinois Institute of Technology, Chicago, Ill.
* To whom correspondence should be addressed. E-mail: mjain{at}rics.bwh.harvard.edu.
The vascular endothelium maintains blood fluidity by inhibiting blood coagulation, inhibiting platelet aggregation, and promoting fibrinolysis. Endothelial cells lose these nonthrombogenic properties on exposure to proinflammatory stimuli. We recently identified the Kruppel-like factor KLF2 as a novel regulator of endothelial proinflammatory activation. Here it is found that KLF2 differentially regulates key factors involved in maintaining an antithrombotic endothelial surface. Overexpression of KLF2 strongly induced thrombomodulin (TM) and endothelial nitric oxide synthase (eNOS) expression and reduced plasminogen activator inhibitor-1 (PAI-1) expression. Furthermore, overexpression of KLF2 inhibited the cytokine-mediated induction of tissue factor (TF). In contrast, siRNA mediated knockdown of KLF2 reduced antithrombotic gene expression while inducing the expression of pro-coagulant factors. The functional importance of KLF2 was verified by in vitro clotting assays. By comparison to control infected cells, KLF2 overexpression increased blood clotting time as well as flow rates under basal and inflammatory conditions. In contrast, siRNA-mediated knockdown of KLF2 reduced blood clotting time and flow rates. These observations identify KLF2 as a novel transcriptional regulator of endothelial thrombotic function.
Key words: endothelium • coagulation • thrombomodulin • transcription
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