Abstract
Activation of the small GTPase RhoA and associated changes in actin dynamics control thrombin‐induced NF‐κB activation and ICAM‐1 expression in endothelial cells. However, the events acting downstream of RhoA to mediate the changes in actin dynamics required for NF‐κB activation and ICAM‐1 expression remain unclear. Here we show that thrombin engages cofilin 1 and mDia1 downstream of RhoA to regulate these responses in endothelial cells. Stimulation of human umbilical vein endothelial cells with thrombin resulted in Ser‐3 phosphorylation/inactivation of cofilin in a ROCK‐dependent manner. RNAi knockdown of cofilin‐1 stabilized the actin filaments and prevented thrombin‐ and RhoA‐induced NF‐κB activity. In parallel experiments, knockdown of mDia1 destabilized the actin filaments and inhibited thrombin‐ and RhoA‐induced NF‐κB activity. Inhibition of NF‐κB activity and ICAM‐1 expression following stabilization and destabilization of actin filaments by these approaches occurred downstream of IκBα degradation and was associated with impaired RelA/p65 nuclear translocation and consequently, RelA/p65 binding to DNA. These findings support the notion thatspecific alterations in actin dynamics induced by thrombin are mediated by concerted actions ofcofilin‐1 and mDia1 and are necessary for RelA/p65 nuclear localization, and thereby ICAM‐1 expression in endothelial cells.This abstract is funded by: ALA, NIH HL067424.
Published Version
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