© 1995 American Heart Association, Inc.
Articles |
Thrombin and Proliferation of Vascular Smooth Muscle Cells
From the Wallenberg Laboratory for Cardiovascular Research, Sahlgren's Hospital, S-413 45 Göteborg, Sweden.
Correspondence to Gunnar Fager, MD, PhD, Wallenberg Laboratory for Cardiovascular Research, Sahlgren's Hospital, S-413 45 Göteborg, Sweden.
Key Words: thrombin • transcription factor • platelet-derived growth factor • fibroblast growth factor • smooth muscle cells
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Introduction |
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Thrombin is a well-established promoter of vascular SMC proliferation in vitro. A similar role has been suggested but not yet proven in vivo. The effect is mediated via selective receptors expressed on vascular SMCs in vitro. Activation of the thrombin receptor leads to a number of intracellular signaling events as well as to stimulation of endogenous PDGF–A chain and bFGF production. The proto-oncogenes c-fos and c-myc, which code for nuclear proteins needed for the induction of proliferation, are induced by PDGF and bFGF. Both growth factors activate protein kinase C. Thrombin rapidly induces only PLC and c-fos but does not activate protein kinase C.
Thrombin-induced receptor activation and intracellular signaling are prevented by substances that block the catalytic and/or receptor binding domains of thrombin. These substances also block thrombin-induced expression of PDGF and bFGF. Furthermore, thrombin-induced proliferation of vascular SMCs is blocked by antibodies to PDGF and FGF. Thus, the possibility must be considered that thrombin influences proliferation of susceptible SMCs by inducing an autocrine or paracrine stimulation via PDGF and/or bFGF.
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Enzymatic Properties of Thrombin |
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Thrombin has important roles in wound healing: promoting the coagulation of blood, accumulation of inflammatory cells, and proliferation of mesenchymal cells.
Enzymatically active thrombin (
-thrombin) is formed from the
circulating precursor prothrombin by hydrolytic cleavage (reviewed in
Reference 11 ). This hydrolysis is initially slow and catalyzed only by
factor Xa. Subsequently, -thrombin activates factor V,
which operates as a cofactor to factor Xa and accelerates the formation
of -thrombin. Furthermore, factor VIII
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