Antioxidants cardiovascular disease and oxidative modifications of lowdensity lipoprotein

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Both lipid-soluble and water-soluble antioxidants present in blood may be important in preventing cardiovascular disease owing to their ability to prevent the oxidation of lipid-protein complexes called lipoproteins. Lipoproteins are extremely important in cardiovascular disease since we know with certainty that high levels of LDL-C cause atherosclerosis, which is the underlying cause of most cardiovascular disease. In contrast, high levels of HDL-C are a negative risk factor for CVD. Atherosclerosis is the gradual build-up of 'plaque' in the arterial wall. LDL-C is the major source of the lipids occurring in these plaques.

There is now considerable evidence that LDL lipids (primarily cholesteryl esters) make their way into plaques by cells in the arterial wall called macrophages. These macrophages take up so much LDL that they become 'foamy' in appearance and are, therefore, called 'foam cells.' This is the very first step (called fatty streak formation) in atherosclerosis and this process begins in childhood. It is surprising, however, that LDL incubated with macrophages does not transform into foam cells. After LDL is oxidized (oxLDL) it will, however, cause macrophages to transform into foam cells. Macrophages have receptors for native LDL but the expression of these receptors is down-regulated by the accumulation of intracellular cholesterol. Unlike native LDL, chemically modified forms of LDL can be taken up by scavenger receptors whose expression is not down-regulated by the accumulation of intracellular cholesterol.

LDL is the primary plasma carrier for both vitamin E and CoQIO, both of which act as antioxidants in LDL by inhibiting lipid peroxidation of lipids containing polyunsaturated fatty acid moieties. Work by Jessup et al. (199O) indicates that most of the endogenous vitamin E in LDL must be oxidized before it is converted into a 'high uptake' form of oxLDL capable of transforming macrophages into foam cells. Since antioxidants, such as vitamin E, prevent the oxidation of LDL (Jessup et al., 199O) it is logical to suggest that antioxidants could prevent foam cell formation and thereby retard the process of atherosclerosis. This suggestion is called the 'oxidative modification hypothesis.' Although most in vitro experiments support this view, not all evidence is supportive (Asmis and Jelk, 2OOO).

Whether or not oxLDL formation occurs in vivo and what the mechanism (s) might be for this oxidation are still open issues (Chisolm and Steinberg, 2OOO). Despite intensive efforts, there is little evidence for the existence of oxLDL in fresh human plasma. This has led to the hypothesis that LDL could be oxidized in the subendothelial space of arteries rather than in plasma. It is significant, therefore, that LDL isolated from human aortic atherosclerotic intima has extremely high levels of 3-nitrotyrosine (Leeuwenburgh et al., 1997). Although the origin of this 3-nitrotyrosine is not clear, it is probably due to the reaction of peroxynitrite (ONOO~) with tyrosine residues in apoBlOO (the primary protein component of LDL). The addition of ONOO~ to LDL or bovine serum albumin in vitro certainly gives rise to 3-nitrotyrosine. Furthermore, LDL-treated ONOO~ undergoes lipid peroxidation accompanied by the oxidation of alpha-tocopherol to alpha-tocopheryl quinone and is converted to a form recognized by macrophage scavenger receptors (Graham et al., 1993; Hogg et al., 1993).

If oxLDL were the source of lipids in atherosclerotic plaques one might expect that these lipids would have a very low content of vitamin E. Paradoxically, Suarna et al. (1995) have found that human atherosclerotic plaques contain relatively large amounts of alpha-tocopherol and ascorbate (a water-soluble antioxidant). Foam cells are not likely, therefore, to be formed by the uptake of large amounts of oxLDL with very low levels of endogenous tocopherol. Nevertheless, Suarna et al. (1995) also found that plaque contains large amounts of oxidized lipids and a significant level of alpha-tocopheryl quinone, an oxidation product of alpha-tocopherol. These data support the view that oxidative stress is an important factor in atherosclerosis but indicate that oxidized lipids in atherosclerotic plaques may not be derived from oxLDL.

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