Structural basis for the pathophysiology of lipoprotein(a) in the athero-thrombotic process.
Lipoprotein Lp(a) is a major and independent genetic risk factor for atherosclerosis and cardiovascular disease. The essential difference between Lp(a) and low density lipoproteins (LDL) is apolipoprotein apo(a), a glycoprotein structurally similar to plasminogen, the precursor of plasmin, the fibrinolytic enzyme. This structural homology endows Lp(a) with the capacity to bind to fibrin and to membrane proteins of endothelial cells and monocytes, and thereby to inhibit plasminogen binding and plasmin generation. The inhibition of plasmin generation and the accumulation of Lp(a) on the surface of fibrin and cell membranes favor fibrin and cholesterol deposition at sites of vascular injury. Moreover, insufficient activation of TGF-beta due to low plasmin activity may result in migration and proliferation of smooth muscle cells into the vascular intima. These mechanisms may constitute the basis of the athero-thrombogenic mode of action of Lp(a). It is currently accepted that this effect of Lp(a) is linked to its concentration in plasma. An inverse relationship between Lp(a) concentration and apo(a) isoform size, which is under genetic control, has been documented. Recently, it has been shown that inhibition of plasminogen binding to fibrin by apo(a) is also inversely associated with isoform size. Specific point mutations may also affect the lysine-binding function of apo(a). These results support the existence of functional heterogeneity in apolipoprotein(a) isoforms and suggest that the predictive value of Lp(a) as a risk factor for vascular occlusive disease would depend on the relative concentration of the isoform with the highest affinity for fibrin.
Anglés-Cano
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Institut National de la Santé et de la Recherche Médicale (INSERM), U. 143, Centre Hospitalier Universitaire de Bicêtre, Université de Paris-Sud, Paris, France. angles@infobiogen.fr
D000818:Animals; D001161:Arteriosclerosis / Q000097:blood / Q000503:physiopathology*; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood / Q000502:physiology*; D008252:Macaca fascicularis; D051379:Mice; D008822:Mice, Transgenic; D011817:Rabbits; D012307:Risk Factors; D013927:Thrombosis / Q000097:blood / Q000503:physiopathology*
D017270:Lipoprotein(a)