Lipoprotein Lp(a) and atherothrombotic disease.
High plasma concentrations of lipoprotein (a) [Lp(a)] are now considered a major risk factor for atherosclerosis and cardiovascular disease. This effect of Lp(a) may be related to its composite structure, a plasminogen-like inactive serine-proteinase, apoprotein (a) [apo(a)], which is disulfide-linked to the apoprotein B100 of an atherogenic low-density lipoprotein (LDL) particle. Apo(a) contains, in addition to the protease region and a copy of kringle 5 of plasminogen, a variable number of copies of plasminogen-like kringle 4, giving rise to a series of isoforms. This structural homology endows Lp(a) with the capacity to bind to fibrin and to membrane proteins of endothelial cells and monocytes, and thereby inhibits binding of plasminogen and plasmin formation. This mechanism favors fibrin and cholesterol deposition at sites of vascular injury and impairs activation of transforming growth factor-beta (TGF-beta) that may result in migration and proliferation of smooth muscle cells into the vascular intima. It is currently accepted that this effect of Lp(a) is linked to its concentration in plasma, and an inverse relationship between apo(a) isoform size and Lp(a) concentrations that is under genetic control has been documented. Recently, it has been shown that inhibition of plasminogen binding to fibrin by apo(a) from homozygous subjects is also inversely associated with isoform size. These findings suggest that the structural polymorphism of apo(a) is not only inversely related to the plasma concentration of Lp(a), but also to a functional heterogeneity of apo(a) isoforms. Based on these pathophysiological findings, it can be proposed that the predictive value of Lp(a) as a risk factor for vascular occlusive disease in heterozygous subjects would depend on the relative concentration of the isoform with the highest affinity for fibrin.
de la Peña-Díaz
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A
Departamento de Hematología, Instituto Nacional de Cardiología Ignacio Chávez, México, D.F., Mexico.
Izaguirre-Avila
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R
Anglés-Cano
E
E
D001054:Apolipoproteins A / Q000235:genetics; D001161:Arteriosclerosis / Q000378:metabolism / Q000503:physiopathology*; D006710:Homocysteine / Q000097:blood; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood / Q000737:chemistry / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011110:Polymorphism, Genetic; D010959:Tissue Plasminogen Activator / Q000378:metabolism
D001054:Apolipoproteins A; D017270:Lipoprotein(a); D017395:Plasminogen Activator Inhibitor 1; D006710:Homocysteine; D010959:Tissue Plasminogen Activator