F. Violi, R. Cangemi and L. Loffredo, University of Rome 'La Sapienza', Italy
Oxidative stress is believed to play a crucial role in the initiation and progression of atherosclerosis disease. Steinberg and colleagues1 were among the first to postulate that modified low-density lipoprotein (LDL) could account for the accumulation of lipid within macrophages, a critical early step in the formation of the atherosclerotic plaque. In the early phases, native LDL may amass in the subendothelial arterial space and may be minimally oxidized by resident vascular cells through the activity of such enzymes as 12/15-lipoxygenase. In turn, this minimally modified LDL leads to the production of chemotactic factors and granulocyte and macrophage colony-stimulating factors, which enhance recruitment of circulating monocytes and their differentiation to macrophages in the vessel wall.
Plaque stability is believed to be influenced by levels of inflammatory mediators locally, which may stimulate expression of a number of proteolytic enzymes that lead to plaque fragility and rupture. These inflammatory actions encourage further oxidization of LDL, leading to both structural and functional changes in the vessel.2 Macrophages avidly accumulate LDL particles modified by oxidation or acetylation through a number of scavenger receptors, including CD36 and scavenger receptors A-I/II, leading to the formation of foam cells and development of the atherosclerotic plaque.3 At the same time, oxidized LDL species are directly toxic to vascular cells, and lead to endothelial injury and dysfunction, disabling, among other things, the intrinsic antiplatelet effects of this protective barrier, as well as the generation of nitric oxide, with deleterious effects on vascular tone and reactivity.2
The importance of oxidized LDL in atherogenesis has been further confirmed by the use of specific antibodies to oxidized LDL, which have been shown to be local to atherosclerotic lesions in the vessel wall.4 Oxidative stress may contribute to atherogenesis by mechanisms that are not necessarily linked to LDL oxidation. For example, free radical oxygen species such as superoxide anion can rapidly react with and inactivate nitric oxide, enhancing proatherogenic mechanisms (e.g. leucocyte adherence to endothelium, impaired vasorelaxation, platelet aggregation).5
Although enzymatic and nonenzymatic oxidation of LDL seems to be involved, its relevance in the evolution of human atherosclerosis is still unclear. An important matter of discussion is the evident discrepancy between experimental and clinical trials with antioxidants, that, in fact, provided divergent results. Most trials with antioxidants in experimental models of atherosclerosis demonstrated that this treatment is able to retard the progression of atherosclerosis while the results of clinical trials are conflicting,5 in that positive as well as negative effects has been reported. The investigation of antioxidants for prevention of atherosclerosis stems from observational trials that demonstrated the existence of an inverse relationship between the consumption of antioxidant vitamins and the risk of cardiovascular events. However, meta-analysis of the observational studies indicated that among antioxidant vitamins, vitamin E was the only one that exerted a beneficial effect against atherosclerotic complications.6
On the basis of these data almost all the trials have been based on the assumption that supplementation with vitamin E would represent a useful approach for preventing cardiovascular disease. However, candidates for antioxidant treatment were not accurately defined: any patient at risk of cardiovascular events has been indiscriminately enrolled in those trials. We argue that antioxidant status represents an important marker of oxidative stress,7 its determination may be useful for better identifying candidates for antioxidant treatment. In order to substantiate this hypothesis, data inherent to oxidative stress and antioxidant status in patients at risk for cardiovascular disease and in patients included in observational and interventional trials have been reviewed. As antioxidant vitamin E has been the subject of the most important research in this field, our analysis is essentially concentrated on the clinical relevance of this vitamin in patients with cardiovascular disease.
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