Structure, function, and genetics of lipoprotein (a)

Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease?

Epidemiological and clinical studies over the past decade have firmly established that elevated plasma concentrations of lipoprotein(a) (Lp(a)) are an important, independent and probably causal risk factor for the development of cardiovascular diseases. Whereas a link between Lp(a) levels and atherosclerotic cardiovascular disease (ASCVD) has been appreciated for decades, the role of Lp(a) in calcific aortic valve disease (CAVD) and aortic stenosis has come into focus only in the past 5 years. ASCVD and CAVD are aetiologically distinct but have several risk factors in common and similar pathological processes at the cellular and molecular levels. Oxidized phospholipids, which modify Lp(a) primarily by covalent binding to its unique apolipoprotein(a) (apo(a)) component, might hold the key to Lp(a) pathogenicity and provide a mechanistic link between ASCVD and CAVD. Oxidized phospholipids colocalize with apo(a)-Lp(a) in arterial and aortic valve lesions and directly participate in the pathogenesis of these disorders by promoting endothelial dysfunction, lipid deposition, inflammation and osteogenic differentiation, leading to calcification. The advent of potent Lp(a)-lowering therapies provides the opportunity to address directly the causality of Lp(a) in ASCVD and CAVD and, more importantly, to provide both a novel approach to reduce the residual risk of ASCVD and a long-sought medical treatment for CAVD.

Oxidized phospholipids as a unifying theory for lipoprotein(a) and cardiovascular disease

Lipoprotein(a) as a risk factor for atherosclerosis and thrombosis: mechanistic insights from animal models

Purpose of reviewLipoprotein(a) is a structurally and functionally unique lipoprotein consisting of the glycoprotein apolipoprotein(a) covalently linked to LDL. Lipoprotein(a) is assembled extracellularly by a two-step mechanism, still incompletely understood, in which initial non-covalent interacti

Structure-function relationships in apolipoprotein(a): insights into lipoprotein(a) assembly and pathogenicity.

Human lipoprotein[a] contains at least two high-molecular-weight, disulfide-linked apolipoproteins, apo[a] and apo B-100. Apo[a] is a highly glycosylated, hydrophilic apoprotein that somewhat resembles plasminogen by containing an extended kringle domain and a carboxyl-terminal serine protease domain. The apo[a] kringle domain is composed of 11 distinct kringle types. Ten of these display high sequence homology to plasminogen kringle 4 (PGK4). The crystallographic coordinates for PGK4 were used to generate three-dimensional molecular models of the apo[a] kringle types, and the lysine-binding region of PGK4 was used to compare the different potential receptor-ligand and ligand-binding sites contained in each different PGK4-like kringle of apo[a]. A receptor-ligand site can be proposed for each kringle type. Potential serine protease cleavage sites, containing arginine-threonine and threonine-arginine, are located on the surface of the kringles. The ligand-binding site of one apo[a] kringle model is almost identical to that of PGK4 and may be a lysine-binding site of apo[a]. Four other apo[a] kringle models appear to have structurally similar lysine-binding sites, but with differences that may influence ligand-polypeptide specificity. Five apo[a] kringle models have ligand-binding sites that probably do not bind lysine; one of these is the highly repeated kringle in the known apo[a] polymorph.

Comparison of ligand-binding sites of modeled apo[a] kringle-like sequences in human lipoprotein[a].

Proposed mechanisms for binding of apo[a] kringle type 9 to apo B-100 in human lipoprotein[a].

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Comparison of ligand-binding sites of modeled apo[a] kringle-like sequences in human lipoprotein[a].

Proposed mechanisms for binding of apo[a] kringle type 9 to apo B-100 in human lipoprotein[a].