Lipoprotein(a): Cellular Effects and Molecular Mechanisms

Abstract

Lipoprotein(a) (Lp(a)) is an independent risk factor for the development of cardiovascular disease (CVD). Indeed, individuals with plasma concentrations >20 mg/dL carry a 2-fold increased risk of developing CVD, accounting for ~25% of the population. Circulating levels of Lp(a) are remarkably resistant to common lipid lowering therapies, and there are currently no robust treatments available for reduction of Lp(a) apart from plasma apheresis, which is costly and labour intensive. The Lp(a) molecule is composed of two parts, an LDL/apoB-100 core and a unique glycoprotein, apolipoprotein(a) (apo(a)), both of which can interact with components of the coagulation cascade, inflammatory pathways, and cells of the blood vessel wall (smooth muscle cells (SMC) and endothelial cells (EC)). Therefore, it is of key importance to determine the molecular pathways by which Lp(a) exerts its influence on the vascular system in order to design therapeutics to target its cellular effects. This paper will summarise the role of Lp(a) in modulating cell behaviour in all aspects of the vascular system including platelets, monocytes, SMC, and EC.

Figure 1

Prothrombotic actions of Lp(a). (a) Plasminogen is activated in a ternary complex comprising fibrin and tPA. Mature plasmin encourages thrombolysis and activates TGFβ. TGFβ has both atheroprotective effects (inhibition of SMC migration and proliferation) and atherogenic effects (inhibition of EC migration, induction of EC cell surface adhesion molecules). (b) Under conditions of elevated plasma Lp(a), plasminogen activation is impaired by multiple mechanisms: Lp(a) competes with plasminogen and tPA for fibrin binding (1). In addition, Lp(a) increases expression of PAI-1 (2) and associates with SERPIN1A (3), both leading to inhibition of tPA. Finally, Lp(a) can associate with α2-macroglobulin, a plasmin inhibitor (4). In combination, all these factors promote a prothrombotic environment.

Figure 2

Inflammatory cell attraction and adhesion. Lp(a) encourages homing of inflammatory cells to sites of Lp(a) deposition within the vascular wall. Circulating cells are attracted to the endothelium by inflammatory cytokines induced by Lp(a). They then bind to and migrate through resident EC via adhesion molecules on the endothelial surface, also induced by Lp(a).

Figure 3

Proliferation and migration of resident vascular wall cells. Lp(a) promotes vascular remodelling by activating multiple signalling pathways within SMC and EC. The response of the cell (e.g., proliferation, migration, or apoptosis) is dependent upon Lp(a) activated signalling cascades that are cell-type specific and dependent upon the oxidation state of the Lp(a) molecule.