New Tricks for Old Dogs

Abstract

Abstract-Thrombin is a serine protease that potently activates platelets and catalyzes the conversion of fibrinogen to fibrin. Thrombin also exerts direct effects on vascular cells, such as smooth muscle cells, via interactions with members of the protease-activated receptor family. Evidence in several animal models implicates thrombin-mediated signaling events in the response to injury that typifies vascular lesion formation in atherosclerosis and restenosis. In this review, we examine the activation of protease-activated receptors by thrombin, the downstream signaling events mediated by these receptors, and the physiological role of thrombin in vascular cells and vascular disease. Key Words: atherosclerosis Ⅲ thrombin Ⅲ vascular biology C onceptually, our understanding of the interface between the thrombosis and hemostasis systems, on one hand, and vessel wall biology, on the other hand, is undergoing a gradual evolution. In its earliest formulation, the interface between these two processes was the inert barrier provided by the vascular endothelium; disruption of this barrier was considered the major stimulus to activation of the coagulation cascade. A level of complexity was added by the discovery that platelet proteins (such as platelet-derived growth factor) and hemostatic factors (such as thrombin) have potent activities on vascular biology independently of any coagulation effects. Conversely, we now know that vascular endothelial and smooth muscle cells (SMCs) produce proteins like tissue factor that modulate the coagulation cascade in the absence of endothelial disruption. This situation becomes even more complex when the effects of coagulation factors on cardiovascular development are considered; the recent demonstration that factor V-deficient mice, which cannot generate thrombin, die in utero of vascular defects in the absence of hemorrhage shows how closely these two systems are interrelated. 1 Not only is the interface between coagulation and vessel wall biology not as simple as it was once thought, the boundaries between these two systems can now hardly be defined at all. It is not surprising, then, that the central molecule in blood coagulation, thrombin, also has profound effects on virtually every aspect of vascular wall biology, including regulation of vessel tone; SMC proliferation, differentiation, and migration; vascular development; atherogenesis; and angiogenesis ( Figure 1). The purpose of this review is to take thrombin out of the narrow context of its role in the coagulation cascade and in platelet function (these aspects of thrombin function have been reviewed elsewhere 2,3 ) and to focus on the roles played by thrombin and its vascular receptors in SMC biology and vascular disease. Although to date pharmacologic inhibition of thrombin has yielded mixed results in the treatment and prevention of atherogenesis, a

Ca2+ Influx Induced by Protease-activated Receptor-1 Activates a Feed-forward Mechanism of TRPC1 Expression via Nuclear Factor-κB Activation in Endothelial Cells

“…Thrombin also activates a variety of cell types, including endothelial cells, smooth muscle cells, and leukocytes (40,41); for example, thrombin induces leukocyte adhesion to endothelial cell surface by increasing the cell surface expression of adhesion molecules ICAM-1, VCAM-1, P-selectin, and E-selectin (18,42,43). Thrombin promotes the expression of ICAM-1 and VCAM-1 via the activation of the transcription factor NF-B in endothelial cells (18,37,42).…”

Thrombin Rapidly Induces Protein Kinase D Phosphorylation, and Protein Kinase C δ Mediates the Activation

“…Thrombin also exerts direct effects on cells to regulate platelet aggregation, endothelial cell activation, and smooth muscle cell (SMC) 1 proliferation via interactions with members of the protease-activated receptor (PAR) family, such as PAR1, PAR2, PAR3, and PAR4, known as G-protein-coupled receptors (2,3). However, the intracellular signaling cascades downstream from the thrombin receptors are surprisingly complex and are still not well understood.…”

cAMP-Response-Element-Binding-Protein-Binding Protein Silencing Inhibits Thrombin-Induced Endothelial Progenitor Cell Migration via Downregulation of CXCR4 Expression

“…PAR-1, PAR-2, PAR-3 and PAR-4 have been identified. 13) Vascular smooth musle cell (VSMC) are known to express PAR-1, PAR-2, and PAR-4 thus potentiating the effect of thrombin in the activation of VSMC proliferation and migration. 14) Previous report has showed that PAR-1 activation on EPC promoted the 3 steps of angiogenesis, including proliferation, migration, and differentiation.…”