Marlys L. Koschinsky* and Randy Ramharack Pages 121 - 138 ( 18 )
Lipoprotein(a) (Lp(a)) is a focus of intensive investigation owing to the correlation that has been demonstrated between elevated plasma Lp(a) levels and the development of a variety of atherosclerotic disorders. The Lp(a) particle resembles LDL and contains apolipoprotein(a) and apolipoproteinB-100 linked by a single disulfide bond. Apolipoprotein(a), which distinguishes Lp(a) from low density lipoprotein both immunologically and biochemically, shares a high level of sequence similarity with the fibrinolytic proenzyme plasminogen. The similarity between the two molecules has prompted speculation that Lp(a) exerts is pathogenic effects by interfering with the normal functions of plasmin(ogen). This has been demonstrated in a number of studies which show that Lp(a) interferes with the tPA mediated activation of plasminogen. This, in tum, has been found to result in the decreased lysis of fibrin clots and in the reduced cleavage of TGF-β and subsequent increased proliferation of smooth muscle cells. The demonstrated localization of Lp(a) in the arterial intima (likely mediated by its extensive interactions with extracellular matrix components) may also facilitate its oxidation and subsequent clearance via the macrophage scavenger receptor, thereby contributing to foam cell formation. Lp(a) can bind to glycosaminoglycans and proteoglycans; these complexes are also ligands for the scavenger receptor. Lp(a) studies have been generally complicated by the high degree of heterogeneity that is associated with the plasma-derived molecule. For example, there are over 35 different apo(a) isoforms, which differ based on the number of identically-repeated plasminogen kringle IV-like sequences in the gene. Additionally, Lp(a) is heterogeneous in its ability to bind to lysine, and likely in its degree of glycosylation, as well as in the apolipoprotein content of the particle. Lp(a) levels are also highly variable in the population. While the mechanism(s) which govern plasma Lp(a) levels are currently unknown, there is evidence to suggest that Lp(a) levels are regulated at the levels of synthesis rather than catabolism. Although Lp(a) levels are genetically determined to a large degree, recent evidence suggests that plasma levels can be modulated by a variety of hormones and pharmacological agents.