Abstract
We investigated the role of RhoA activation and its mechanism in plasminogen activator inhibitor-1 (PAI-1) gene expression induced in endothelial cells by monocyte adhesion. Isolated human peripheral blood monocytes were added to cultured human coronary endothelial cells. Monocyte adhesion to endothelial cells increased PAI-1 expression at the transcriptional level and activated RhoA which was accompanied by an increase in the activity of geranylgeranyl transferase I (GGTase I), an enzyme responsible for geranylgeranylation, and actin stress fiber formation. Inhibition of RhoA by C3 exoenzyme or by adenovirus-mediated expression of N19RhoA, as well as by pravastatin, prevented the upregulation of PAI-1 induced by monocyte adhesion. GGTI-286, an inhibitor of GGTase I, prevented the monocyte-induced RhoA activation and PAI-1 expression in endothelial cells. Monocyte attachment induced an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) in endothelial cells and Ca(2+) chelation prevented the increased promoter activity and expression of PAI-1 induced by monocyte adhesion. C3 exoenzyme and GGTI-286 also suppressed endothelial intracellular Ca(2+) mobilization and Ca(2+) entry induced by monocytes. The present study shows that GGTase I plays a role in the RhoA activation in endothelial cells induced by monocyte adhesion and that GGTase I-mediated Ca(2+) signaling may contribute to RhoA-dependent PAI-1 gene expression.
Published Version
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