Extensión superficial

It is unlikely that the oxidation o f LDL occurs to any great extent in the circulation due to the presence o f antioxidants such as ascorbate. However, the presence o f fragments o f apo-B (Schuh et al, 1978), increased levels o f lipid peroxides and thiobarbituric acid-reactive substances (TEARS; Yagi,

1987) and a low level o f modified LDL immunoreactivity (Salmon et al,

1987) has been demonstrated in human plasma, indicating that some degree o f oxidative modification o f LDL occurs in plasma. Furthermore, a modified LDL fraction has been isolated from the plasma o f Lp(a)-negative subjects which was more electronegative that the bulk o f LDL and was more rapidly internalised by macrophages indicating that the fraction represented oxidised LDL (Avogaro et al, 1988).

Several lines o f evidence exist to suggest the presence o f oxidatively modified LDL in atherosclerotic lesions. LDL extracted from aortas o f WHHL rabbits and from human atherosclerotic lesions showed an increased electrophoretic mobility, increased fragmentation o f apo-B and an increased hydrated density indicating that oxidation had occurred (Daugherty et al,

modified residues found in apo-B o f OXLDL (Haberland et al, 1988; Paiinski et al, 1989) or against OXLDL itself (Palinski et al, 1989) show immunoreactivity in rabbit aortic atherosclerotic lesions, but not in normal areas o f aortic tissue. Furthermore, monoclonal antibodies against human OXLDL reacted with atheromatous lesions from WHHL rabbits but not with arterial tissue from normal rabbits (Boyd et al, 1989), and monoclonal antibodies raised to WHHL rabbit arterial plaque homogenates were specific for OXLDL (Mowri et al, 1988).

Although the demonstration o f OXLDL in lesions in vivo supports the hypothesis that oxidation o f LDL is important in atherosclerosis, it does not prove that OXLDL plays a causal role. Studies using probucol, a lipid- lowering drug with powerful antioxidant properties (Parthasarathy et al,

1986), have provided more convincing evidence for the role o f OXLDL in the pathogenesis o f atherosclerosis. Treatment o f WHHL rabbits with probucol has been shown to inhibit the rate o f uptake and modification o f native LDL in areas with lesions and to decrease the rate o f progression o f atherosclerosis (Tawara et al, 1986; Carew et al, 1987; Kita et al, 1987; Steinberg et al, 1988; Daugherty et al, 1991). In addition, probucol may promote the regression o f established plaques (Yamamoto et al, 1986; Nagano et al, 1992). The protective effect o f probucol was found to be independent o f its lipid-lowering properties and was attributed to its antioxidant action (Carew et al, 1987; Nagano et al, 1992). It has been demonstrated that the antioxidant butylated hydroxytoluene (BHT), a close chemical analogue o f probucol, can also slow the progression o f atheroselerosis in cholesterol-fed rabbits (Bjorkhem et al, 1991). Probucol has also been shown to reduce plasma lipid peroxide levels in hyperlipidaemic patients (Paterson et al, 1992). However, in contrast, one

study found no protective role o f probucol on atherosclerosis in cholesterol- fed rabbits when the cholesterol-lowering effect was controlled for (Stein et al, 1989).

It is possible that probucol may have actions other than its antioxidant or lipid-lowering effects which contribute to its effectiveness in decreasing the rate o f atherosclerosis. It has been suggested that probucol directly affects macrophages to inhibit the uptake o f LDL (Yamamoto et al, 1986), or may increase the rate o f cholesterol efflux from lipid-laden macrophages (Goldberg and Mendez, 1988). Furthermore, administration o f probucol has been shown to suppress intimai thickening o f the carotid artery following balloon catheter injury which may be due to the inhibition o f cell migration or cell proliferation (Shinomiya et al, 1992).

The mechanism by which in situ modification o f LDL in the arterial intima may lead to the formation o f foam cells has not been established. If extensive modification occurs then uptake by the scavenger receptor pathway may be involved. It has been demonstrated that modified LDL from human atherosclerotic plaques was more susceptible to degradation by the scavenger receptor pathway in cultured macrophages (Yla-Herttuala et al, 1989). In addition, macrophage-derived foam cells isolated from rabbit atherosclerotic lesions degrade OXLDL, promote the oxidation o f LDL and contain oxidation-specific lipid-protein adducts, indicating that in vivo arterial wall macrophages express receptors for modified LDL and are capable o f oxidising LDL even when maximally loaded with cholesterol (Rosenfeld et al, 1991).

In contrast, another study demonstrated that degradation o f LDL from human atherosclerotic lesions by macrophages occurred via a low affinity non-scavenger receptor mechanism (Morton et al, 1986), and that extracts o f

atherosclerotic plaques could modify LDL in vitro in a way which led to an increased non-saturable, non-receptor mediated degradation in cultured macrophages (H off and O'Neil, 1988). It was concluded that the modification o f LDL by plaque components which was responsible for the interaction with macrophages did not involve oxidation, since the uptake by macrophages persisted in the presence o f BHT (H off and O'Neil, 1988), but reactions between the apo-B and aldehydes or the formation o f complexes with arterial proteoglycans may be involved.