Structural basis for the pathophysiology of lipoprotein(a) in the athero-thrombotic process

Abstract

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-ß 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. Correspondence

Specificity, diversity, and regulation in TGF‐β superfamily signaling

“…1), and by binding of LAP to mannose-6-phosphate receptors (17,19 and references therein). Lipoprotein Lp(a) inhibits activation of plasminogen to plasmin and thereby negatively affects activation of TGF-␤ (reviewed in ref 22 and references therein). Other mechanisms that have been implicated in activation of latent TGF-␤ are deglycosylation of LAP (23), exposure to reactive oxygen species (24), or acidic cellular microenvironments (25).…”

Lipoprotein (a): a Unique Independent Risk Factor for Coronary Artery Disease

“…This allows Lp(a) to bind to fibrin and to the membrane proteins of endothelial cells and monocytes. Since Lp(a) resembles both LDL and plasminogen, it could possibly act as a link between atherosclerosis and thrombosis [41]. The accumulation of Lp(a) on the surface of fibrin and cell membranes as well as the inhibition of plasmin generation favors the deposition of fibrin and cholesterol at sites of vascular injury.…”

“…Short apo(a) alleles increased Lp(a) levels, thus favoring atherosclerosis. Also, since the inverse relationship between apo(a) size & Lp(a) is not linear, this suggests a functional diversity among the Hepatic secretion lower for large apo(a) isoforms & since most individuals are heterozygous for two different isoforms, so typically the smallest isoform dominates in plasma apo(a) isoforms [41]. Another study by Hervio et al [59] suggested that the variable number of kringles in apo(a) influences its ability to bind to fibrin.…”

Transgene Tiere

“…In letzter Zeit wurde auch versucht, andere Krankheiten im Kaninchenmodell zu studieren und Proteine in vivo in Milch bzw. Blut zu 16.2 Transgene Kaninchen 173 exprimieren (Angles-Cano 1997, Taylor 1997. Kaninchen haben zudem eine große Bedeutung für die Generierung von Antiseren, und sind das einzige kleinere Tier, das mit dem humanen Immundefizienz Virus (HIV) infizierbar ist.…”