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Thrombin induces ICAM‐1 expression via store‐operated Ca2+ influx signaling in endothelial cells
Author(s) -
Bair Angela Mae,
Freichel Marc,
Vogel Stephen,
Flockerzi Veit,
Malik Asrar,
Tiruppathi Chinnaswamy
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a70-c
Subject(s) - thrombin , icam 1 , microbiology and biotechnology , thrombomodulin , chemistry , signal transduction , intracellular , endothelial stem cell , endothelium , biology , endocrinology , biochemistry , immunology , in vitro , platelet
Thrombin‐induced endothelial cell surface ICAM‐1 expression plays a critical role in the pathogenesis of lung vascular injury. NF‐κB activation is required for stable thrombin‐induced ICAM‐1 expression. We explore the role of Ca 2+ signaling in the mechanism of NF‐κB‐dependent ICAM‐1 expression human pulmonary artery endothelial cells (HPAEC). We show that IP 3 ‐receptor antagonist, 2‐APB inhibits thrombin‐induced increase in intracellular Ca 2+ ([Ca 2+ ] i ), NF‐κB activation and ICAM‐1 expression in HPAEC. 2‐APB failed to inhibit TNF‐α‐induced ICAM‐1 mRNA. Thrombin‐induced increase in [Ca 2+ ] i is dependent on both ER stored‐Ca 2+ release and Ca 2+ ‐store depletion‐mediated Ca 2+ influx occurring via TRP channels in endothelial cells. To address the importance of Ca 2+ influx signal, we measured thrombin‐induced NF‐κB activation and ICAM‐1 transcript expression in the absence of Ca 2+ influx in HPAEC. Thrombin‐induced p65 nuclear translocation and ICAM‐1 mRNA expression were reduced by preventing Ca 2+ influx. Since TRPC4 is the essential component of SOC in mouse endothelial cells, we measured NF‐κB activation and ICAM‐1 expression in TRPC4 null (TRPC4 − / − ) mice. Isolated perfused mouse lung studies showed impaired thrombin‐induced NF‐κB activation in TRPC4 − / − compared to wild type (WT). Thrombin‐induced ICAM‐1 mRNA expression was reduced in lung endothelial cells (LEC) from TRPC4 − / − compared to WT LEC. Thus, thrombin‐induced store‐operated Ca 2+ influx signaling is critical in the mechanism of NF‐ B‐dependent ICAM‐1 expression in endothelial cells.