Role of the thrombin receptor in restenosis and atherosclerosis.
Thrombus generation is central to thrombosis at vascular lesion sites, including post-PCTA acute reocclusion and chronic restenosis. Thrombin stimulates platelet activation, monocyte and neutrophil chemotaxis, and endothelial production of prothrombotic factors. The varied physiologic effects of thrombin are due to the widespread presence of thrombin receptors in many cell types. The receptor is uniquely activated: thrombin binds to the receptor at the thrombin anion-binding exosite, the receptor ligand ("tethered ligand") apparently being a sequence of 6 amino acids (SFLLRN). Thus, peptides corresponding to the sequence of the tethered ligand can stimulate almost all functions of native thrombin itself. Several intracellular signaling pathways have been identified as important in the restenosis process: the G protein-related pathway, cyclic adenosine monophosphate (cAMP) mediator pathway, and tyrosine kinase activation pathway. In situ hybridization has demonstrated an increase in thrombin receptor mRNA throughout the period of neointimal and vascular lesion development. The mechanism of this increase is unknown, but may be mediated by multiple inflammatory modulators. Several strategies have been tested in animal models for inhibiting thrombin: (1) Hirudin not only prevents thrombin from cleaving fibrinogen, but also prevents thrombin receptor activation. (2) Thrombin receptor antagonist peptides block platelet aggregation effects of thrombin. (3) Mono- and polyclonal antibodies inhibit thrombin receptor activation. (4) Antisense oligonucleotides block thrombin receptor expression.
Baykal
D
D
Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
Schmedtje
J F
JF
Runge
M S
MS
D000208:Acute Disease; D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D003324:Coronary Artery Disease / Q000209:etiology* / Q000503:physiopathology / Q000628:therapy; D003327:Coronary Disease / Q000209:etiology* / Q000503:physiopathology / Q000628:therapy; D006801:Humans; D018179:Receptors, Thrombin / Q000502:physiology*; D012008:Recurrence
D018179:Receptors, Thrombin