on March 2, 2006
Published online before print March 2, 2006, doi: 10.1161/01.ATV.0000215638.53414.99
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Submitted on August 29, 2005
Accepted on February 15, 2006
Kruppel-Like Factor 2 Inhibits Protease Activated Receptor-1 Expression and Thrombin-Mediated Endothelial Activation
Zhiyong Lin ;
From the Program in Cardiovascular Transcriptional Biology, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
* To whom correspondence should be addressed. E-mail: mjain{at}rics.bwh.harvard.edu.
Objective--The serine protease thrombin can dramatically alter endothelial gene expression in a manner that confers a proinflammatory phenotype. Recent studies have identified the Kruppel-like factor 2 (KLF2) as a critical regulator of endothelial gene expression. Herein, we provide evidence that KLF2 inhibits thrombin-mediated endothelial activation via alterations in expression of its principal receptor protease-activated receptor-1 (PAR-1).
Methods and Results--Forced expression of KLF2 in human umbilical vein endothelial cells potently inhibited the ability of thrombin to induce multiple prothrombotic factors (tissue factor, CD40L, plasminogen activator inhibitor-1), cytokines/chemokines (eg, monocyte chemotactic protein-1, interleukin-6 [IL-6], IL-8), and matrix degrading enzymes (eg, matrix metalloproteinases 1, 2, and 9). Mechanistically, KLF2 inhibits PAR-1 expression and, as a consequence, thrombin-mediated nuclear factor 
B (NF-B) nuclear accumulation and DNA binding. Conversely, small interfering RNA-mediated knockdown of KLF2 increases PAR-1 expression and thrombin-mediated induction of NF-B activation.
Conclusion--These studies identify KLF2 as a novel regulator of PAR-1 expression and thrombin action in endothelial cells.
Key words: Kruppel • thrombin • PAR-1 • transcription • endothelial cells
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