Oxidative Stress in Atherogenesis: Basic Mechanisms and Problems of Therapy with Antioxidants

Background: Oxidative stress is recognized as an essential mechanism of atherogenesis and plaque progression. However, the origin of increased free radical production has not yet been well described. Furthermore, therapy with antioxidants has not shown convincing results.

Objective: To consider questions concerning the impact of oxidative stress, and the effects and usefulness of antioxidants.

Animals And Methods: Atherosclerotic plaques were induced in rabbits by feeding them a cholesterol-rich diet (2%) for six weeks. Thereafter a normal diet was given up to 68 weeks. Body weight, food intake, plasma lipid concentration and antioxidative capacity were determined at various time intervals. Aortic plaque size, morphology and radical production were determined in groups of animals killed after six, 14, 21, 29, 40 and 74 weeks, and compared with values in untreated controls. Chemiluminescent methods were used to determine antioxidative capacity of plasma, generation of free radicals and redox reactivity of various antioxidants.

Results: Antioxidative capacity, occurrence of modified low density lipoprotein and generation of free radicals indicated oxidative stress during plaque progression; however, they showed different correlations to cellular components of the plaques. Furthermore it was shown that some antioxidants have both anti- and pro-oxidative properties.

Conclusions: Oxidative stress during atherogenesis seems to correlate with different phases of plaque development and can be associated with different types of reactive species. Because plaque remodelling and stabilization may also be a phase of increased free radical generation, therapeutic antioxidants must exert specific and selective activity; in particular, whether their oxidized form acts pro-oxidatively must be determined.