ATHEROSCLROSIS: ROLE OF OXIDIZED LDL (low density lipoprotein )

The causal role of hypercholesterolemia (due primarily to an increase in LDL) in the aetiology of atherosclerosis implies that monocyte and macrophages become foam cells by LDL uptake, presumably via the LDL receptor-mediated pathway. However, in vitro experiments have shown that this is not the case. Monocytes do possess LDL receptors, but these become down-regulated as soon as the intracellular cholesterol content increases. It is now known that in addition to LDL receptors, monocytes also have receptors for various forms of modified LDL provide the long-sought link between atherosclerosis, lipoproteins, and the clotting system. In vitro evidence suggests that Lp(a) has both thrombogenic and anti- fibrinolytic potential. However, in vivo evidence has thus far remained tenuous. There is evidence, though still controversial to some extent, that microthrombi on the vessel wall become incorporated into atherosclerotic plaques. Fibrinogen and fibrin are found in these loci in roughly the same proportion as cholesterol; Lp(a) has also been shown to be present. Apo(a) is shown to have a higher tissue:plasma ratio than apo B, suggesting that Lp(a) has an even higher affinity for the vessel wall than has LDL, and thus confirms its atherogenecity. The kringle 4 domain is known to bind to fibrinogen, although somewhat weakly. It is not unlikely that the apo(a) protein, with 37 copies of this kringle might bind to fibrinogen or fibrin under certain conditions in vivo. Thus when Lp(a) finds its way into the fissured arterial wall following endothelial damage, it might adhere to fibrin, forming a complex that precipitates out and remains within the vessel wall. Lp(a) might also block proteolysis of fibrin by inhibiting the activation of plasminogen by tissue plasminogen activator, thereby inhibiting cleavage of fibrin clots. The receptor, called the scavenger receptor, has been cloned and its presence demonstrated in foam cell- packed areas of atheromatous lesions. Various lines of direct experimental evidence have established the role of oxidised LDL in athero- genesis beyond reasonable doubt and support the concept that native LDL in vivo is avidly taken up by macrophages via this scavenger receptor-mediated pathway, after oxidative modification.