PATHOPHYSIOLOGICAL IMPLICATION OF THE STRUCTURAL DOMAINS OF LIPOPROTEIN(A)

Numerous epidemiological studies have shown that lipoprotein(a) (Lp(a) ) is an independent risk factor for the premature development of cardi ovascular disease. In spite of such evidence, the structural and funct ional features of this atherogenic, cholesterol-rich particle are not clearly understood. We have demonstrated the presence of two distinct structural domains in apolipoprotein(a) (apo(a)), which are linked by a flexible and accessible region located between kringles 4-4 and 4-5. We have isolated the Lp(a) particle following removal of the N-termin al domain by proteolytic cleavage; the residual particle, containing t he C-terminal domain (comprising the region from Kr 4-5 to the proteas e domain), is linked to apo B-100 by disulphide linkage, and is termed 'mini-Lp(a)'. Mini-Lp(a) exhibited the same binding affinity to fibri n as the corresponding Lp(a). This finding indicated that the kringles responsible for fibrin binding are restricted to Kr 4-5 to Kr 4-10, a n observation consistent with the failure of the N-terminal domain to bind to fibrin. N-terminal fragments of apo(a) have been detected in t he urine of normal subjects, thereby indicating that part of the catab olism of Lp(a), which is largely indeterminate, could occur via the re nal route. (C) 1997 Elsevier Science Ireland Ltd.