Kruppel-like factor 2 inhibits protease activated receptor-1 expression and thrombin-mediated endothelial activation.
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).


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.
Lin
Zhiyong
Z
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Hamik
Anne
A
Jain
Rajan
R
Kumar
Ajay
A
Jain
Mukesh K
MK
D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D044463:Receptor, PAR-1 / Q000235:genetics; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors
C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D016328:NF-kappa B; D044463:Receptor, PAR-1; D013917:Thrombin; D010975:Platelet Aggregation Inhibitors