Lipoprotein(a) the Insurgent: A New Insight into the Structure, Function, Metabolism, Pathogenicity, and Medications Affecting Lipoprotein(a) Molecule

Figure 4

Different theories of how Lp(a) causes atherosclerosis. Early lesions (1) Lp(a) enters the vascular wall and is oxidized by MPO, 12/15 LO, LPO, NADPH, O₂⁻, and H₂O₂. (2) OxLp(a) and OxPLs constitute a substantial increase in monolayer permeability, resulting in increased Lp(a) and LDL entry into the vascular wall. (3) OxLp(a) and OxPLs bind to the E-type prostaglandin receptor (EP2) receptor, causing deposition of connecting segment 1 (CS-1). Additionally, OxLp(a) stimulates the expression of cell adhesion molecules (ICAM, VCAM E-selectin) that bind to monocytes on the endothelial cell surface. (4) OxLp(a) may also activate specific disintegrin and metalloproteinases (ADAMs) to cause the release of active heparin binding epidermal growth factor (HBEGF) and activation of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2), causing IL-8 and monocyte chemotactic protein (MCP)-1 production. (5) These chemokines simplify access of the attracted monocytes to the artery wall. (6) OxPL build-up causes monocytes to differentiate into M1, dendritic cells, Mox cells, and foam cells. Advanced lesions (7) macrophages engulf OxLp(a) through its scavenger receptor CD36 to form the foam cell. (8) Ox-Lp(a) and Lp(a) also induce aberrant proliferation, migration, and phenotype switching of smooth muscle cells (SMCs). (9) OxLp(a) stimulates CD36 to activate TLR2/6, which activates ERK and results in ER stress-induced loss of integrity of the mitochondria, which eventually leads to apoptosis. (10) Apoptotic cells provide more OxPLs and stimulate angiogenesis. (11) OxLp(a) may stimulate LKB1/AMPK/ mTOR activity and induce apoptotic cell removal by macrophages. (12) Necrotic core formation and vessel wall rupture. (13) Macrophage and OxLp(a) cause increased platelet aggregation. (14) Apo(a) binding to PLG binding sites blocks the interaction between PLG and tissue PLG activator (tPA). (15) Lp(a) increases the production and activity of tPA inhibitor-1 (PAI-1), which eventually leads to a decrease in fibrinolysis (16). Lp(a) increases the expression of TF and inhibits the potent inhibitory effect of tissue factor pathway inhibitor (TFPI), which leads to thrombosis. Dotted lines: hypothesized pathways.