Elevated levels of lipoprotein(a) [Lp(a) ) are associated with an increased risk of coronary artery disease, but the mechanism(s) by which Lp(a) potentiates atherogenesis is incompletely understood. The recent determination of the cDNA sequence of apo(a), however, has provided unique insight into the structure of Lp(a) and its potential mechanistic relevance for atherothrombosis. Apo(a) demonstrates a remarkable homology to human plasminogen, containing multiple kringle or lysine-dependent fibrin binding domains. In this application, we outline a proposal to investigate the functional consequences of Lp(a) binding to adhesive and matrix proteins on the cellular and extracellular fates of Lp(a). The objectives of this proposal are: 1) to examine the binding of Lp(a) to fibrin(ogen); in particular, to characterize the domains of Lp(a)/apo(a) and of fibrin(ogen) responsible for this binding interaction, to compare the fibrinogen binding properties of the various apo(a) isoforms and cloned kringle 4-like domains, and to assess the role of Lp(a)/apo(a) glycosylation in fibrin(ogen) binding; 2) to investigate the functional consequences of Lp(a) binding to fibrinogen on fibrin polymerization and platelet aggregation; 3) to examine the binding of Lp(a) to collagen and elastin, its modulation by fibrin(ogen), and the importance of Lp(a) interactions with matrix proteins in the accumulation of Lp(a) in the vessel wall; and 4) to investigate the interaction of Lp(a) and fibrin(ogen) with the classic LDL receptor, scavenger receptor, and MAC-1 receptor on monocytes/ macrophages. The experiments outlined in this proposal should provide new insight into the molecular and cellular mechanisms by which thrombotic and atherogenic factors interact. Understanding these mechanisms may provide new information useful in the prevention and treatment of atherosclerotic disease.