BIOLOGY OF PLATELETS
Endothelial cells play a critical role in thromboregulation by promoting the assembly of a membrane bound fibrinolytic system. Our studies have been designed to characterize the molecular mechanisms controlling this system in health and disease. Cultured endothelial cells synthesize and secrete tissue plasminogen activator which binds to a distinct membrane receptor in a manner that preserves catalytic activity. Circulating plasminogen, the major fibrinolytic zymogen, binds to the endothelial surface and is converted to the membrane bound enzyme plasmin. Lipoprotein (a), an atherogenic lipoprotein particle contains a plasminogen like apolipoprotein (a). This lipoprotein interferes with endothelial cell fibrinolysis by inhibiting plasminogen binding and down regulates plasmin formation. Lipoprotein (a) induces upregulation of plasminogen activator inhibitor mRNA expression and further augments localized thrombogenesis. This system which links chronic thrombogenesis and atherosclerosis may play a major role in the pathogenesis of premature accelerated coronary and cerebral artery occlusive disease. The normal physiologic role of lipoprotein (a) is unknown. Inflammatory cytokines appear to play a major role in regulating this system. Our goals are to define the molecular and cell biologic mechanisms controlling these events.