The Roles of Lipoprotein(a) in Atherosclerosis - Minding the Knowledge Gaps.
Although the association of lipoprotein(a) (Lp(a)) with coronary heart disease was reported over 60 years ago, and subsequent studies have identified a causal and independent role for Lp(a) in disease, many fundamental unanswered questions persist surrounding the biology of this enigmatic lipoprotein. There remain critical questions surrounding the structure and metabolism of Lp(a) and the unique biochemical properties of Lp(a) that drive its pathogenic properties in the vasculature. These questions are critical to address as we rapidly approach the availability of drugs that can specifically lower Lp(a).
Lp(a) is more atherogenic than low-density lipoprotein (LDL) on a per-particle basis, and this is largely thought to be due to the presence of the unique glycoprotein apolipoprotein(a) (apo(a)) on Lp(a). Moreover, Lp(a) is enriched in proinflammatory lipids such as oxidized phospholipids (OxPL) and diacylglycerols (DAG). A large body of in vitro data as well as emerging transgenic Lp(a) mouse data and human imaging studies have provided evidence for a multitude of proatherosclerotic mechanisms for Lp(a), exerted on inflammatory/immune cell types such as monocytes and macrophages, and on vascular cells including smooth muscle cells and endothelial cells. These effects would be expected to exacerbate atherosclerosis and promote a rupture-prone plaque phenotype. In addition, Lp(a) may directly contribute to atherothrombosis by potentiating platelet responses and the coagulation cascade and causing the formation of a lysis-resistant clot architecture. While outcomes trials of potent Lp(a)-lowering therapies may soon reveal whether these treatments prevent atherothrombotic events in high-risk patients, further animal model and human studies will be required to understand the nature of these beneficial effects.
Lp(a) is more atherogenic than low-density lipoprotein (LDL) on a per-particle basis, and this is largely thought to be due to the presence of the unique glycoprotein apolipoprotein(a) (apo(a)) on Lp(a). Moreover, Lp(a) is enriched in proinflammatory lipids such as oxidized phospholipids (OxPL) and diacylglycerols (DAG). A large body of in vitro data as well as emerging transgenic Lp(a) mouse data and human imaging studies have provided evidence for a multitude of proatherosclerotic mechanisms for Lp(a), exerted on inflammatory/immune cell types such as monocytes and macrophages, and on vascular cells including smooth muscle cells and endothelial cells. These effects would be expected to exacerbate atherosclerosis and promote a rupture-prone plaque phenotype. In addition, Lp(a) may directly contribute to atherothrombosis by potentiating platelet responses and the coagulation cascade and causing the formation of a lysis-resistant clot architecture. While outcomes trials of potent Lp(a)-lowering therapies may soon reveal whether these treatments prevent atherothrombotic events in high-risk patients, further animal model and human studies will be required to understand the nature of these beneficial effects.