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
Arteriosclerosis, Thrombosis, and Vascular Biology 2006, 26 (5): 1185-9

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 kappaB (NF-kappaB) nuclear accumulation and DNA binding. Conversely, small interfering RNA-mediated knockdown of KLF2 increases PAR-1 expression and thrombin-mediated induction of NF-kappaB activation.

CONCLUSIONS: These studies identify KLF2 as a novel regulator of PAR-1 expression and thrombin action in endothelial cells.

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