Tissue Factor-Factor VIIa complex induces cytokine expression in coronary artery smooth muscle cells.
OBJECTIVE
Within atherosclerotic lesions Tissue Factor (TF)-Factor VIIa (FVIIa) not only contributes to thrombotic events but also alters vascular remodeling through enhancement of migration. Moreover, the TF-FVIIa-FXa complex activates protease-activated receptors (PAR). TF/FVIIa/PAR-2 signaling has also been shown to promote proliferation and metastasis of tumor cells. Since coagulation factors promote inflammation which plays a major role during atherosclerosis as well as tumor metastasis this study sought to investigate the effects of FVIIa on the inflammatory response in vascular cells.


RESULTS
FVIIa induces interleukin-8 (IL-8) and IL-6 in primary smooth muscle cells (SMC), which was correlated to the expression of TF and PAR-2 as shown by immunoassay and qRT-PCR. The effect was dose-dependent and required TF, the proteolytic activity of FVIIa and PAR-2. Secondary effects of downstream coagulation factors were excluded. No proinflammatory FVIIa effect was observed in endothelial cells (EC) and mononuclear cells (MNC), expressing either TF or PAR-2. In atherosclerotic lesions mRNA expression of PAR-1, PAR-2 and IL-8 was elevated compared to healthy vessels indicating a role for PAR-1 and PAR-2 signaling in atherosclerosis.


CONCLUSIONS
In addition to the procoagulant and promigratory role of the TF-FVIIa complex we identify a proinflammatory role of FVIIa in human SMC dependent on expression of TF and PAR-2 that provides yet another link between coagulation and inflammation.
Demetz
G
G
Deutsches Herzzentrum und 1. Medizinische Klinik, Technische Universität München, Lazarettstr. 36, 80636 Munich, Germany.
Seitz
I
I
Stein
A
A
Steppich
B
B
Groha
P
P
Brandl
R
R
Schömig
A
A
Ott
I
I
D001777:Blood Coagulation; D002462:Cell Membrane / Q000378:metabolism; D003331:Coronary Vessels / Q000166:cytology*; D016207:Cytokines / Q000096:biosynthesis*; D015942:Factor VIIa / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D034622:RNA Interference; D044463:Receptor, PAR-1 / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism*
D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D013925:Thromboplastin; D015942:Factor VIIa