The oxidative theory of
atherosclerosis relies on the modification of
low density lipoproteins (LDLs) in the vascular wall by
reactive oxygen species. Modified LDLs, such as oxidized LDLs, are thought to participate in the formation of early atherosclerotic lesions (accumulation of foam cells and fatty streaks), whereas their role in advanced lesions and atherothrombotic events is more debated, because
antioxidant supplementation failed to prevent
coronary disease events and mortality in intervention randomized trials. As oxidized LDLs and oxidized
lipids are present in atherosclerotic lesions and are able to trigger cell signaling on cultured vascular cells and macrophages, it has been proposed that they could play a role in
atherogenesis and atherosclerotic
vascular remodeling. Oxidized LDLs exhibit dual biological effects, which are dependent on extent of lipid peroxidation, nature of oxidized
lipids (oxidized
phospholipids,
oxysterols,
malondialdehyde, α,β-unsaturated hydroxyalkenals), concentration of oxidized LDLs and uptake by
scavenger receptors (e.g. CD36, LOX-1, SRA) that signal through different transduction pathways. Moderate concentrations of mildly oxidized LDLs are proinflammatory and trigger cell migration and proliferation, whereas higher concentrations induce cell growth arrest and apoptosis. The balance between survival and apoptotic responses evoked by oxidized LDLs depends on cellular systems that regulate the cell fate, such as
ceramide/
sphingosine-1-
phosphate rheostat, endoplasmic reticulum stress, autophagy and expression of pro/antiapoptotic
proteins. In vivo, the intimal concentration of oxidized LDLs depends on the influx (
hypercholesterolemia, endothelial permeability), residence time and
lipid composition of LDLs, oxidative stress intensity, induction of defense mechanisms (
antioxidant systems,
heat shock proteins). As a consequence, the local cellular responses to oxidized LDLs may stimulate inflammatory or anti-inflammatory pathways, angiogenic or antiangiogenic responses, survival or apoptosis, thereby contributing to plaque growth, instability, complication (intraplaque
hemorrhage, proteolysis, calcification, apoptosis) and
rupture. Finally, these dual properties suggest that oxLDLs could be implicated at each step of
atherosclerosis development, from early fatty streaks to advanced lesions, depending on the nature and concentration of their oxidized
lipid content.