Impact of Antioxidant Therapy

Because lipoprotein oxidation is thought to play a major role in atherogenesis, it could be expected that intervention with antioxidants would be protective against atherosclerotic disease. Although antioxidant studies in four different animal models of atherosclerosis (rabbit, mouse, hamster, and monkey) mainly showed positive results (67,82), several large-scale, double-blind, placebo-controlled trials evaluating the effects of different antioxidant compounds on cardiovascular outcome were inconsistent. For instance, two large primary prevention studies, the ATBC Study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study) (83) and the PPP (Collaborative Group ofthe Primary Prevention Project) (84), reported that vitamin E treatment had no apparent effect on MI, CVD, or stroke. The Cambridge Heart Antioxidant Study trial, which included 2002 patients with angiographically confirmed CAD, showed a significant reduction in composite end point (i.e., cardiovascular death and nonfatal AMI), with no effects on total mortality, mortality from CVD, and other causes (85). However, the Grupo Italiano per lo Studio della Sopravvivenza nell 'Infarto miocardico Prevenzione Investigators (GISSI) and Heart Outcomes Prevention Evaluation (HOPE) trials, which included a large number of patients with MI or subjects at high risk of cardiovascular events found no benefits of antioxidant supplementation (86,87). A meta-analysis of 15 randomized trials revealed no benefit of antioxidant supplementation on CVD end points (88). Nevertheless, in extremely high-risk patients with renal insufficiency requiring chronic dialysis, supplementation with vitamin E appears to be associated with a significant decrease in cardiovascular end points (MI, stroke, peripheral vascular disease, and unstable angina) (89).

Fig. 3. Illustration of various steps that 12/15-LO and 5-LO may participate in throughout atherogen-esis and aneurysm formation. 12/15-LO affects monocyte-endothelial interactions, possibly through products of12/15-LO. 12/15-LO in macrophages participates in oxidative modification of aggregated LDL, bound to extracellular matrix (ECM) potentially via an LDL receptor-related protein 1 (LRP1)-mediated selective uptake of cholesteryl esters. 12/15-LO modulates Th1 cytokine interleukin-12 (IL-12) production in macrophages. 5-LO converts arachidonic acid into LTs, which are potent proinflammatory lipid mediators. 5-LO may play a role in regulating matrix metalloproteinase 2 (MMP-2), which breaks down the elastic lamina of the vascular wall and can lead to aneurysm formation. The 5-LO pathway may be important for inflammatory chemokine macrophage inflammatory protein 1-a (MIP-1 a) production in macrophages. (Reprinted from ref. 91 with permission from Elsevier, Copyright 2004.)

Fig. 3. Illustration of various steps that 12/15-LO and 5-LO may participate in throughout atherogen-esis and aneurysm formation. 12/15-LO affects monocyte-endothelial interactions, possibly through products of12/15-LO. 12/15-LO in macrophages participates in oxidative modification of aggregated LDL, bound to extracellular matrix (ECM) potentially via an LDL receptor-related protein 1 (LRP1)-mediated selective uptake of cholesteryl esters. 12/15-LO modulates Th1 cytokine interleukin-12 (IL-12) production in macrophages. 5-LO converts arachidonic acid into LTs, which are potent proinflammatory lipid mediators. 5-LO may play a role in regulating matrix metalloproteinase 2 (MMP-2), which breaks down the elastic lamina of the vascular wall and can lead to aneurysm formation. The 5-LO pathway may be important for inflammatory chemokine macrophage inflammatory protein 1-a (MIP-1 a) production in macrophages. (Reprinted from ref. 91 with permission from Elsevier, Copyright 2004.)

Although the results oflarge antioxidant trials were disappointing, on the basis ofexperi-mental and epidemiological studies, it seems justified to conclude that oxLDL may indeed play a key role in the generation of inflammatory processes in atherosclerotic lesions. This is supported by a recent prospective study showing that increased antioxidative capacity as assessed by glutathione peroxidase 1 levels was associated with improved outcome (90).

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