Lipoprotein(a) and cardiovascular disease

Abstract

Elevated plasma levels of lipoprotein(a) (Lp(a)) are a prevalent, independent, and causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease. Lp(a) consists of a lipoprotein particle resembling low density lipoprotein and the covalently-attached glycoprotein apolipoprotein(a) (apo(a)). Novel therapeutics that specifically and potently lower Lp(a) levels are currently in advanced stages of clinical development, including in large, phase 3 cardiovascular outcomes trials. However, fundamental unanswered questions remain concerning some key aspects of Lp(a) biosynthesis and catabolism as well as the true pathogenic mechanisms of the particle. In this review, we describe the salient biochemical features of Lp(a) and apo(a) and how they underlie the disease-causing potential of Lp(a), the factors that determine plasma Lp(a) concentrations, and the mechanism of action of Lp(a)-lowering drugs.

Keywords: apolipoprotein(a); atherosclerotic cardiovascular disease; calcific aortic valve disease; lipoprotein metabolism; lipoprotein(a); thrombosis.

Figure 1.. Kringle organization and functional domains of apo(a).

Apo(a) consists of multiply-repeated domains homologous to plasminogen kringle 4, followed by a single kringle 5-like domain and an inactive protease-like domain. Kringle UIV type 2 in apo(a) (KIV2) is present in between 3 and over 40 copies and underlies Lp(a) isoform heterogeneity in the population. Some apo(a) KIV types contains weak or strong lysine binding sites (LBS) that play roles in Lp(a) assembly, binding to Lp(a) to substrates, and addition of oxidized phospholipid (oxPL). Apo(a) KIV9 contains the single unpaired cysteine that mediates disulfide bonding to apoB100 in the Lp(a) particle. Also indicated is the presence of N- and O-linked glycosylation in each kringle and in the interkringle regions, respectively, and the site of proteolytic cleavage by elastase or MMP-12.

Figure 2.. Assembly of Lp(a).

Within the hepatocyte, apo(a) KIV7 and 8 form an initial non-covalent interaction with specific lysine residues in the amino-terminal domain of apoB100. Covalent bond formation occurs extracellularly and is catalyzed by a specific oxidase enzyme. Also depicted is the ligand-induced conformation change in apo(a) that accelerates covalent Lp(a) assembly [26].

Figure 3.. Biosynthesis and catabolism of Lp(a).

Novel therapeutics that specifically lower Lp(a) act by destabilizing the LPA mRNA that encodes apo(a) or by blocking the initial non-covalent interaction between apo(a) and apoB. After secretion of the non-covalent apo(a)-apoB complex, covalent Lp(a) is formed, and the circulating particle is taken up by the liver by one or more receptors. Candidates for which there is the most evidence are LDL receptor (LDLR), scavenger receptor-B1 (SR-B1) and the plasminogen receptor Plg-R_KT. The current phase of clinical trial development is listed n parentheses after the drug name. ASO, antisense oligonucleotide; siRNA: small interferening RNA; SM, small molecule.

Figure 4.. Potential pathogenic mechanisms of Lp(a).

Lp(a) has pro-atherosclerotic, pro-calcific (primarily leading to calcific aortic valve disease), and pro-thrombotic mechanisms of action. Virtually all of the pro-atherosclerotic and pro-calcific effects have been shown to be mediated by the oxPL covalently associated with apo(a) KIV10. The individual pathogenic mechanisms have been primarily demonstrated through in vitro and ex vivo studies (see [115–117] for details). EC, endothelial cells; oxPL: oxidized phospholipids; IL: interleukin; SMC, smooth muscle cell; TFPI, tissue factor pathway inhibitor; Plg: plasminogen; PAI-1: plasminogen activator inhibitor type 1.