Elsevier

Atherosclerosis

Volume 133, Issue 1, August 1997, Pages 1-6
Atherosclerosis

Review article
Pathophysiological implication of the structural domains of lipoprotein(a)

https://doi.org/10.1016/S0021-9150(97)00111-1Get rights and content

Abstract

Numerous epidemiological studies have shown that lipoprotein(a) (Lp(a)) is an independent risk factor for the premature development of cardiovascular disease. In spite of such evidence, the structural and functional 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-terminal domain by proteolytic cleavage; the residual particle, containing the C-terminal domain (comprising the region from Kr 4-5 to the protease 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 fibrin 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, an observation consistent with the failure of the N-terminal domain to bind to fibrin. N-terminal fragments of apo(a) have been detected in the urine of normal subjects, thereby indicating that part of the catabolism of Lp(a), which is largely indeterminate, could occur via the renal route.

Introduction

Lipoprotein (a) (Lp(a)) was first described in 1963 by Berg [1]. Since that time Lp(a) has gained considerable clinical interest as a result of both retrospective and prospective studies which have demonstrated that this cholesterol-rich particle constitutes an independent risk factor for the premature development of cardiovascular disease (see [2]for review). Lp(a) appears to express its atherothrombogenicity through different mechanisms. Several studies have shown that Lp(a) and apolipoprotein(a) (apo(a)) deposit in the arterial wall 3, 4, and the importance of such accumulation is directly linked to their plasma Lp(a) concentration. A unique property of Lp(a) as compared to other atherogenic particles concerns its implication in the fibrinolytic process. The structural homology between Lp(a) and plasminogen (see below) is reflected in the role of Lp(a) as a competitive inhibitor of the action of plasminogen in the fibrinolytic process. Such competition has been demonstrated in several in vitro experiments 5, 6, 7, 8and also in vivo in the cynomolgus monkey [9]and in transgenic mice [10]. Finally, Lp(a) could potentially act in promoting the proliferation of smooth muscle cells [11]. Although Lp(a) may play an important role in the development of atherosclerosis, little is known of its structural and functional features, and of their relationship to the pathophysiology of atherothrombosis.

Section snippets

Structure of Lp(a)

The Lp(a) particle closely resembles low-density lipoprotein (LDL) in both lipid composition and in its content of a single copy per particle of apolipoprotein B-100 (apo B-100). However, the presence of apo(a), a highly glycosylated protein which is disulfide-linked to apo B-100 12, 13differentiates Lp(a) from LDL. The primary structure of apo(a) has been deduced from the sequence of a cloned apo(a) cDNA and revealed a striking homology to plasminogen (PLG) [14]. The apo(a) cDNA contained

Apo(a) size polymorphism

Originally, six isoforms of apo(a), differing in size, were described [26]. Since then, and with the development of more resolutive electrophoretic procedures, 34 distinct apo(a) protein isoforms have been identified 27, 28. The apo(a) gene exhibits the same degree of polymorphism as demonstrated by pulse gel electrophoresis of genomic DNA [27]. Therefore the size heterogeneity of apo(a) at the protein level is controlled by a series of autosomal alleles at a single locus. Moreover, the

Structural domains of apo(a) in the Lp(a) particle

A possible experimental approach to the exploration of the conformation of the apo(a) protein in Lp(a) involved evaluation of the reactivity of different monoclonal antibodies directed against epitopes in the particle. Such an approach has been successfully used to define the conformation of apo B-100 in different lipoprotein particles, including Lp(a) 34, 35. However, the elevated number of repeated sequences in apo(a) prevented such an approach. Folded structural domains of proteins are

Pathophysiological aspects of Lp(a) domains

It has been demonstrated that Lp(a) is able to compete with PLG for binding to both fibrin 38, 39and cell surfaces 40, 41. Other studies have also suggested that Lp(a) can inhibit the direct activation of plasminogen by t-PA [42]and the plasmin generating activity of streptokinase [43]. These complex and multiple interactions can be promoted by various domains of Lp(a) and/or by different kringles. The ability of each purified domain to bind either to intact or plasmin-degraded fibrin was

Implications of the existence of distinct domains for the catabolism of Lp(a)

Oida et al. [45]have shown that fragments of apo(a) could be detected in urinary samples of nephrotic patients. Very recently, Mooser et al. [46]have developed this finding further. By an approach involving specific antibodies and partial proteolysis of Lp(a), they demonstrated that urinary fragments originated only from the N-terminal part of apo(a). The pattern of urinary fragments was constant irrespective of both the apo(a) isoform and the circulating Lp(a) concentration in the subjects

Acknowledgements

This work was partly supported by Bayer-AG (Contrat de Valorisation INSERM-BAYER No. 94 009).

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