2.2.4. Oxidative modification of LDL
There is much evidence indicating that oxidized LDL (Ox-LDL) is present in atherosclerotic lesions in vivo (Ylä-Herttuala 1998). First of all, LDL isolated from atherosclerotic lesions is in part oxidatively modified (Ylä-Herttula et al. 1989). Second, immunological techniques have demonstrated that atherosclerotic lesions contain materials reactive with antibodies generated against Ox-LDL (Haberland et al. 1988, Palinski et al. 1989, Rosenfeld et al. 1990). Third, serum contains autoantibodies against Ox-LDL (Palinski et al. 1989, Salonen et al. 1992). Fourth, treatment with antioxidants can prevent the development or slow the progression of atherosclerosis (Carew et al. 1987, Kita et al. 1987, Steinberg 1997a).
In principle, any modified LDL in plasma could be rapidly removed by hepatic sinusoidal cells (Kupffer cells), which contain abundant scavenger receptors. Moreover, a variety of antioxidants remain in plasma. Therefore, it was presumed that Ox-LDL mainly occurred locally in the arterial wall after entrance of normal LDL, whereby it was sequestered from antioxidants in plasma (Steinberg et al. 1989, Witztum and Steinberg 1991). However, recent studies have suggested that very small amounts of Ox-LDL are also present in plasma (see review from Nielsen 1999). These changes could have occurred elsewhere, or during a previous transient passage through the artery wall. Such minimally modified LDL might then be "primed" for more rapid oxidative modification on a subsequent entry into the intima. Therefore, Ox-LDL in the arterial wall can be derived both from normal LDL oxidized locally in the arterial intima and from Ox-LDL in plasma (Nielsen 1999).
Lipid peroxidation presumably starts in the polyunsaturated fatty acids (PUFA) forming an ester bond with LDL-surface PLs, and then propagates to core lipids, resulting in oxidative modification not only of the PUFA, but also of the cholesterol moiety (mostly CE) and modification and degradation of apoB (Witztum 1994).
Therefore, a wide variety of biologically active molecules can be formed, including oxidized sterols, oxidized fatty acids, and PL and protein derivatives generated by adduct formation with breakdown products of oxidized fatty acids. For example, malondialdehyde and 4-hydroxynonenal can subsequently react with lysine residues in apoB. Such adducts, and others, presumably create the epitopes on apoB that lead to recognition by scavenger receptors on macrophages.
In culture, all the vascular cells can initiate oxidation of LDL, but the relative contributions of ECs, monocytes and macrophages, or smooth muscle cells (SMC) to such modification in vivo are unknown (Heinecke 1998, Ylä-Herttuala 1998). In vitro, LDL can bind to copper which can promote rapid lipid peroxidation. However, it is not known whether sufficient free copper and iron, or complexes of these metals, exist in vivo to promote LDL peroxidation, although intact ceruloplasmin can act as a prooxidant.
Therefore, several mechanisms are probably involved, and even the same cell type may use different pathways. For example, release of superoxide anion from ECs or SMCs might be responsible for initiation of oxidation in some settings, and thiols in others (Heinecke et al. 1986).
In macrophages, enhanced 15-lipoxygenase activity could generate increased cellular lipid hydroperoxides, which could be transferred to extracellular LDL, providing the "seed" that would lead to enhanced lipid peroxidation (Heinecke 1998).
The antioxidant defences that prevent oxidation of LDL need to be defined. The antioxidant content of the LDL particle is critical for its protection (Esterbauer et al. 1992) and, theoretically, if sufficient lipophilic antioxidants were present, the LDL particles would be protected from even profound oxidant challenge. In vivo, whether or not LDL becomes oxidized is a question of the balance between the extent of the prooxidant challenge and the capacity of the antioxidant defenses.
Although Ox-LDL is found in man, there are no conclusive intervention studies in man to support a quantitatively important role for this process. The ongoing antioxidant trials will no doubt add more beneficial evidence in the role of atherosclerosis prevention.
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