Elevated levels of lipoprotein(a), which consists of apolipoprotein(a) [apo(a)] covalently linked to a low-density lipoprotein-like moiety, is an independent risk factor for the development of atherosclerosis. We show that a recombinant form of apo(a) [r-apo(a)] binds strongly to fibronectin and fibrinogen, weakly to laminin, and not at all to von Willebrand factor, vitronectin, or collagen type IV. In contrast to the binding of plasminogen to fibronectin, r-apo(a) binding does not appear to be mediated by rysine-dependent interactions, based on the inability of e-aminocaproic acid concentrations up to 0.2 mol/L to significantly decrease r-apo(a) binding to fibronectin. Plasminogen competed weakly for the binding of L ipoprotein(a) [Lp(a)] has been identified as an independent risk factor for the development of coronary heart disease (for review, see References 1 and 2). Marked inherited variability has been observed with respect to plasma Lp(a) levels, which vary from less than 1 to more than 100 mg/dL. Roughly 25% of the human population possesses Lp(a) levels above an apparent coronary risk threshold of 30 mg/dL, which more than doubles the risk of developing coronary heart disease.3 "
6With respect to both lipid composition and the presence of apolipoprotein (apo) B-100, Lp(a) closely resembles low-density lipoprotein (LDL). Lp(a) is clearly distinguishable from LDL, however, by the presence of apo(a), which likely confers the unique structural and functional properties attributed to Lp(a). Human apo(a) consists of multiple tandem repeats of a sequence closely resembling plasminogen kringle IV, followed by sequences exhibiting =90% identity to the kringle V and protease regions of plasminogen.7 Apo(a) is covalently linked to LDL extracellularry in plasma by a single disulfide bridge mediated in apo(a) by an unpaired cysteine present in the penultimate kringle IV repeat.8 Given the high degree of similarity between Lp(a) and both plasminogen and LDL, it has been hypothesized that Lp(a) contributes to the de- Correspondence to Dr M.L. Koschinsky, Department of Biochemistry, Queen's University, Kingston, Ontario, Canada K7L 3N6.© 1994 American Heart Association, Inc.r-apo(a) to fibronectin, whereas r-apo(a) completely abolished plasminogen binding. The 29-and 38-kd heparin-binding thermolysin fragments of fibronectin, previously identified as the lipoprotein(a) binding domains, were digested with trypsin, and a peptide that retained the ability to bind r-apo(a) was isolated; the sequence of the peptide (AVTTIPAPTDLK) corresponds to the amino terminus of the 29-and 38-kd domains. A synthetic peptide with this sequence was able to compete effectively with fibronectin for r-apo(a) binding.