Low density lipoprotein oxidation and atherogenesis: from experimental models to clinical studies

Oxidative modifications of low-density lipoproteins (LDL) ("oxidation hypothesis") appears to be the pathophysiologic mechanism implicated in early atherogenesis. Oxidized LDL (ox-LDL) may also induce several pro-atherogenic mechanisms, such as the regulation of vascular tone, by interfering with nitric oxide, the stimulation of cytokines and chemotactic factors (MCP-1, M-CSF, VCAM-1, etc.) and transcription factors (AP1 and NFk beta). These phenomena complicate the spectrum of direct and indirect actions of ox-LDL. The immunogenicity of ox-LDL was used to generate monoclonal antibodies against many epitopes of ox-LDL, such as malondialdehyde-lysine (MDA-2) or 4-hydroxynonenal-lysine (NA59). These antibodies showed the occurrence of ox-LDL in vivo. Another issue is the role of the humoral and cellular immune system in atherogenesis, in particular whether the immune response to ox-LDL enhances or reduces early atherogenesis. Moreover, the induction of autoantibodies against ox-LDL and the recognition by "natural" antibodies, and the use of the those antigens to screen human sera may serve as a marker of atherosclerosis. In this review, we have stressed the importance of methodologic approach in the assessment of LDL-oxidation and the fact that lipoprotein (a) may also undergo oxidative modifications. Several clinical conditions are associated with increased rate of LDL-oxidation. Recently, we have observed the presence of LDL oxidation-specific epitopes in human fetal aortas. Antioxidants studies in primary prevention of atherosclerosis have produced contradictory results. This may be explained in part by the selection of patients who had advanced lesions and were often smokers. New trails suggest that antioxidants be administered early in children. Lastly, antioxidant studies in the secondary prevention of coronary heart disease (CHAOS, WACS, and HOPE) show clear evidence of the benefits of antioxidants in reducing new cardiovascular events.