Thrombin and protease-activated receptors (PARs) in atherothrombosis

Abstract

Thrombin is a multifunctional serine protease generated at the site of vascular injury that transforms fibrinogen into fibrin, activates blood platelets and elicits multiple effects on a variety of cell types including endothelial cells, vascular smooth muscle cells (VSMC), monocytes, T lymphocytes and fibroblasts. Cellular effects of thrombin are mediated by protease-activated receptors (PARs), members of the G protein-coupled receptors that carry their own ligand which remains cryptic until unmasked by proteolytic cleavage. Thrombin signalling in platelets contributes to haemostasis and thrombosis. In normal arteries PARs are mainly expressed in endothelial cells, while their expression in VSMC is limited. Endothelial PARs participate in the regulation of vascular tone, vascular permeability and endothelial secretory activity while in VSMC they mediate contraction, migration, proliferation, hypertrophy and production of extracellular matrix. PARs contribute to the pro-inflammatory phenotype observed in endothelial dysfunction and their up-regulation in VSMC seems to be a key element in the pathogenesis of atherosclerosis and restenosis. In the last years a myriad of studies have emphasized the critical role of PAR signalling in thrombin mediated effects in haemostasis, inflammation, cancer and embryonic development. Lately, PARs have become a therapeutic target to inhibit platelet aggregation and thrombosis. Early data from a clinical trial (TRA-PCI) to evaluate safety and efficacy of a potent new oral thrombin receptor antagonist (TRA) have promisingly indicated that overall TRA treatment reduces adverse event rates without an increase in bleeding risk. In this paper we review cellular responses triggered by thrombin and their implication in vascular pathophysiology.

Platelet biogenesis and functions require correct protein O-glycosylation

“…We also examined whether the platelets from EHC Cosmc −/y mice could be activated by the agonist thrombin. After stimulation through the protease activated receptor (PAR-1) pathway, activated platelets normally spread and release P-selectin on the cell surface, and convert integrin αIIbβ3 (GPIIb/IIIa) into its active form (conformation) (15). Scanning electron microscopy (SEM) revealed that wild-type platelets display peripheral flattening, lamellipodia, and filopodia extensions on fibrinogen, whereas EHC Cosmc −/y platelets were rounded with few filopodia and greatly reduced spreading (Fig.…”

Thrombin induced connective tissue growth factor expression in rat vascular smooth muscle cells via the PAR-1/JNK/AP-1 pathway

“…Thrombin is implicated in the process of vascular remodelling in atherosclerosis and restenosis [3] . Thrombin can stimulate the formation of collagen in a PAR-1-dependent mechanism in vascular smooth muscle cells (VSMCs) [4] .…”

The Hemostatic System in Arterial Thrombosis and Coronary Atherosclerosis

“…All of these mediators are involved in the pathophysiology of atherosclerosis and contribute to the initiation, formation, progression and destabilization of coronary atherosclerotic plaques. Its signaling mechanisms with a pro-atherogenic impact on the arterial vessel wall are mostly established via Proteinase-activated receptors (PARs) 27,28 .…”