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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2005.)
© 2005 American Heart Association, Inc.

Thrombosis

Endogenous NO Blockade Enhances Tissue Factor Expression via Increased Ca²⁺ Influx Through MCP-1 in Endothelial Cells by Monocyte Adhesion

Takayuki Sakamoto; Toshiyuki Ishibashi; Nobuo Sakamoto; Koichi Sugimoto; Kensuke Egashira; Hiroshi Ohkawara; Kenji Nagata; Keiko Yokoyama; Masashi Kamioka; Toshihiro Ichiki; Naotoshi Sugimoto; Masahiko Kurabayashi; Koji Suzuki; Yoh Takuwa; Yukio Maruyama

From the First Department of Internal Medicine (T.S., T.I., N.S., K. Sugimoto, H.O., K.N., K.Y., M. Kamioka, Y.M.), Fukushima Medical University, Fukushima; the Department of Cardiovascular Medicine (K.E., T .I.), Graduate School of Medical Sciences, Kyushu University, Fukuoka; the Department of Molecular and Cellular Physiology (N.S., Y.T.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; the Department of Medicine and Biological Science (M. Kurabayashi), Gunma University Graduate School of Medicine, Maebashi; and the Department of Molecular Pathobiology (K. Suzuki), Mie University School of Medicine, Japan.

Correspondence to Toshiyuki Ishibashi, MD, First Department of Internal Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan. E-mail masaishi{at}fmu.ac.jp

Objective— Ca²⁺ plays an important role in tissue factor (TF) gene expression. We investigated the role of endogenous nitric oxide (NO) in the induction of TF expression in endothelial cells (ECs) by monocyte adhesion and the mechanisms of NO action.

Methods and Results— Inhibition of endogenous NO by N-nitro-L-arginine methyl ester (L-NAME) enhanced TF promoter activity and protein expression induced in human coronary ECs by monocyte adhesion, as well as EC surface TF activity. L-NAME also induced monocyte chemoattractant protein-1 (MCP-1) expression, which was blocked by an NO donor, NOC18. Exogenous MCP-1 enhanced TF expression induced by monocyte adhesion, whereas adenovirus-mediated expression of the mutant MCP-1, 7ND, abolished the L-NAME enhancement of TF expression induced by monocyte adhesion. Monocyte attachment to L-NAME–treated ECs increased Ca²⁺ influx, which was prevented by NOC18, anti–MCP-1 antibody or 7ND. These results indicate that the binding of increased MCP-1 induced by endogenous NO blockade to CCR2 mediated the enhancement of Ca²⁺ influx only when monocytes adhered to ECs, which upregulated TF expression in ECs triggered by monocyte adhesion.

Conclusion— MCP-1/CCR2 may play a role in Ca²⁺ influx-dependent TF regulation in the monocyte–EC interaction in the impairment of NO synthesis.

Endogenous NO blockade increased Ca²⁺ influx and TF expression in ECs when monocytes adhered to them. This was inhibited by the mutant MCP-1, 7ND. These suggest a role for MCP-1/CCR2 in endogenous NO blockade in procoagulant activity via Ca²⁺ influx–dependent TF expression in monocyte–EC interaction.

Key Words: calcium • endothelium • nitric oxide • MCP-1 • tissue factor

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