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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1185.)
© 2006 American Heart Association, Inc.

Thrombosis

Kruppel-Like Factor 2 Inhibits Protease Activated Receptor-1 Expression and Thrombin-Mediated Endothelial Activation

Zhiyong Lin; Anne Hamik; Rajan Jain; Ajay Kumar; Mukesh K. Jain

From the Program in Cardiovascular Transcriptional Biology, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Mukesh K. Jain MD, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115. 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.

Thrombin binding to its receptor PAR1 can regulate endothelial cell activation. Here we show that the transcription factor KLF2 inhibits thrombin action. Gain and loss of function studies reveal that KLF2 can regulate PAR1 expression and NF-B activation. These observations have important implications for thrombin action in vascular biology.

Key Words: Kruppel • thrombin • PAR-1 • transcription • endothelial cells

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