Inserm, Institut national de la santé et de la recherche médicale
Faculté de pharmacie, Aix Marseille Université

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Type I collagen induces tissue factor expression and matrix metalloproteinase 9 production in human primary monocytes through a redox-sensitive pathway

Poitevin S, Garnotel R, Antonicelli F, Gillery P, Nguyen P. 2008, 6/9 (Sept) - Journal of Thrombosis and Haemostasis. Pages : 1586–1594. Impac factor : 6.29


Background :  Tissue factor (TF), the main trigger of coagulation cascade, is a major component of the atherosclerotic plaque. Matrix metalloproteinases (MMPs) are recognized as key mediators of extracellular matrix remodeling during inflammation. It was recently emphasized that both TF and MMP-9 were overexpressed in atherosclerotic plaques, suggesting a role of both molecules in plaque instability and thrombogenicity. Objective : The present study was designed to determine whether human monocytes could co-express TF and MMP-9 when the cells interact with type I collagen, a major component of the extracellular matrix and atherosclerotic plaque.

Methods :  Human monocytes were isolated by elutriation and incubated in collagen I-coated plates. Tissue factor and MMP-9 expression were examined using real-time reverse transcription-polymerase chain reaction, flow cytometry, western blot and zymography. The activation of nuclear factor-κ B (NF-κB) and the role of reactive oxygen species (ROS) in TF and MMP-9 production was studied using gel shift experiments, antioxidants pyrrolidine dithiocarbamate (PDTC) and N-acetyl-cysteine (NAC), and apocynin (a specific inhibitor of the NADPH oxidase).

Results : Type I collagen induced TF expression and increased MMP-9 production. In addition, the pro-inflammatory tumor necrosis factor-α (TNF-α), produced in response to collagen I, increased MMP-9 production. PDTC and NAC inhibited NF-κB activation during monocyte interaction with collagen I. Finally, both antioxidants and apocynin decreased the expression of TF, TNF-α, and MMP-9. Conclusions : These results indicate a new mechanism in the monocyte expression of TF and MMP-9 in response to collagen I involving a ROS-dependent pathway linked to the activation of the NADPH oxidase.