Antioxidants in LDL

Taken from: http://ethesis.helsinki.fi/

2.2.9. Antioxidants in the pathogenesis of atherosclerosis

As discussed in section 2.2.7, Ox-LDL is involved in several steps of atherosclerosis. It is believed that antioxidants can interfere to different extents with these steps (Faggiotto et al. 1998). Kleinveld et al. (1993) reported that 18 weeks of pravastatin or simvastatin administered to 23 hypercholesterolemic patients (15 men, 8 women) decreased LDL cholesterol levels by 36% and significantly reduced the rate and extent of copper-catalyzed LDL oxidation. LDL particles after therapy were changed in composition to contain less lipid relative to protein, possibly rendering the particle less susceptible to oxidation (Lavy et al. 1991). HMG-CoA reductase inhibitors rather than reducing LDL levels and changing its particle composition, may also be of antioxidant importance. In this regard, Giroux et al. (1993) reported that simvastatin diminished superoxide anion formation and LDL oxidation by human macrophages in tissue culture. Fruebis et al. (1994) have found that atherosclerosis in WHHL rabbits is inhibited by probucol (a potent antioxidant) but not by its analogue with similar structure. Thus, for any given prooxidant stress, there may be a threshold of protection that must be achieved. Protection of LDL from oxidation could increase nitric oxide bioavailability and improve endothelium-dependent vasomotor, anti-inflammatory, and anticoagulant properties of the endothelium (Guetta and Cannon 1996). Recently, Yasunari et al. (1999) observed that antioxidants probucol and vitamin E prevent smooth muscle cell migration and proliferation via reducing intracellular oxidative stress. Since endogenous antioxidants (superoxide dismutase, H₂O₂-removing enzymes, and metal binding proteins) may become inadequate to prevent LDL oxidation, exogenous antioxidants (diet-derived or supplemented) would seem, therefore, important to maintain such effect in vivo. The direct provision of lipophilic antioxidants into the LDL particle should be the most effective strategy. The most abundant natural antioxidant in LDL is a-tocopherol (Esterbauer et al. 1992), and supplementation of the diet with vitamin E can increase the vitamin E content of LDL and lead to enhanced protection of such LDL from in vitro oxidation. The vitamin E content in LDL particles is positively correlated with oxidation resistance (Tesoriere et al. 1998). However, in man, supplementation at about 1.2 g per day saturates the LDL, and at this degree of enrichment (about a 2 1/2-fold increase) the lag time for CD formation, a sensitive index of susceptibility to lipid peroxidation, is only prolonged by 50% (Reaven and Witztum 1996). Tikkanen et al. (1998) have observed that soybean phytoestrogen intake prolonged the lag time by 20 min. However, we do not know if this degree of lag time prolongation is sufficient to protect LDL under all conditions and its correlation to the prevention of CAD. For example, in hypercholesterolaemia, the residence of LDL in the artery is prolonged. If the pro-oxidant stress is continuous, more potent antioxidant activity would be required. Beta-carotene is the next most common antioxidant in LDL (Esterbauer et al. 1992) and theoretically should provide enhanced antioxidant protection. However, data have not supported this effect even when the b-carotene content was increased more than 20-fold by dietary enrichment (Heinecke 1998, Anderson et al. 1998). By contrast, the administration of probucol to volunteers, such that the probucol content of the LDL is 2-4 mg/mg of LDL protein, can lead to near-total protection against oxidative stress for as long as 16 hours. Vitamin C, a water-soluble antioxidant, also provides significant protection for LDL in vitro, presumably by maintaining or regenerating vitamin E in the LDL particle in its reduced antioxidant state.

Another strategy to protect LDL against oxidation is to reduce its content of PUFA by dietary substitution with oleic acid (Reaven et al. 1993). The diet-enriched flavonoids and isoflavonoids, may have great nutritional benefits against atherosclerosis as they appear to constitute a major source of dietary antioxidants (Hertog et al. 1993).

A reduction in prooxidant activity can also be achieved by enhancing the antioxidant content of cells, for example, by enriching them with ascorbate, or with vitamin E or b-carotene. Navab et al (1991) have developed a co-culture of ECs and SMCs that can oxidatively modify LDL. Enrichment of this culture with vitamin E, or b-carotene, decreases the ability of the cells to modify LDL.

In theory, antioxidant protection could be achieved with changes in lifestyle, diet and even with pharmacological approach. Despite the impressive ability of lipid-soluble antioxidants to block atherosclerosis in hypercholesterolemic animals, some studies are controversial because these antioxidants may have other antiatherogenic effects such as a hypolipidemic effect which may confound the conclusion. However, randomized clinical trials will eventually resolve the question as to whether these antioxidants deserve greater importance in inhibition of atherosclerosis.