Integral Role of RhoA Activation in Monocyte Adhesion–Triggered Tissue Factor Expression in Endothelial Cells

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 23; no. 4; pp. 681 - 687
• Main Authors: Ishibashi, Toshiyuki, Sakamoto, Takayuki, Ohkawara, Hiroshi, Nagata, Kenji, Sugimoto, Koichi, Sakurada, Sotaro, Sugimoto, Naotoshi, Watanabe, Atai, Yokoyama, Keiko, Sakamoto, Nobuo, Kurabayashi, Masahiko, Takuwa, Yoh, Maruyama, Yukio
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.04.2003; Hagerstown, MD Lippincott
• Subjects: Biological and medical sciences; Cardiology. Vascular system; cdc42 GTP-Binding Protein - metabolism; Cell Adhesion - physiology; Coculture Techniques; Coronary Vessels - cytology; Culture Media, Conditioned - pharmacology; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Enzyme Activation; Enzyme Inhibitors - pharmacology; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Guanosine Triphosphate - metabolism; Heart; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Humans; Intercellular Adhesion Molecule-1 - biosynthesis; Intercellular Adhesion Molecule-1 - genetics; Medical sciences; Monocytes - physiology; NF-kappa B - metabolism; Promoter Regions, Genetic; Protein Prenylation - drug effects; Protein Processing, Post-Translational - drug effects; Protein Transport; rac GTP-Binding Proteins - metabolism; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - genetics; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - physiology; Thromboplastin - biosynthesis; Thromboplastin - genetics; Transcription, Genetic; Human; Endothelial cell; Monocyte; Pathogenesis; monocyte adhesion; Tissue factor; Cardiovascular disease; Statin derivative; Adhesion; Vascular disease; statin; Atherosclerosis; Rho; Cell
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000065194.00822.C7

OBJECTIVE—The role of Rho activation in the regulation of tissue factor (TF) is not clear. This study was undertaken to investigate this in endothelial cells induced by monocyte adhesion. METHODS AND RESULTS—Isolated human peripheral blood monocytes were added to cultured human coronary endothelial cells. Monocyte adhesion to endothelial cells increased the levels of TF antigen in the endothelial cells. The results of transient transfection of the human TF promoter/luciferase gene into endothelial cells indicated that the increase in endothelial expression of the TF gene caused by monocyte adhesion occurred at the transcriptional level. The upregulation of TF was inhibited by statins, and the suppressive effect of statins was reversed by geranylgeranylpyrophosphate. Monocyte adhesion rapidly upregulated the membrane translocation and GTP/GDP exchange of RhoA, but not of Cdc42 or Rac, in endothelial cells. Rho inhibition by C3 exoenzyme or adenovirus-mediated expression of N19RhoA prevented the endothelial upregulation of TF caused by monocyte adhesion, and this was mimicked by Rho-kinase inhibitors. Moreover, monocyte adhesion increased the phosphorylation of nuclear factor-κB p65 in endothelial cells, and this was prevented by statins and Rho inhibition. CONCLUSIONS—Our study shows that RhoA activation plays an integral role in TF expression in endothelial cells.