Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 106, Issue -, Pages 118-133Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2017.02.006
Keywords
Oxidized LDLs; Atherosclerosis; Scavenger receptor; LOX-1; Oxidative stress; Inflammation; Proliferation; Apoptosis; Angiogenesis; Oxidative stress; Lipid peroxidation products; Tyrosine kinase receptors; 4-hydroxynonenal; Ceramide; Sphingosine 1-phosphate; ER stress; Autophagy; miRNAs
Funding
- Inserm (Institut National de la Sante et de la Recherche Medicale)
- ANR-Carina [ANR-12-BSV1-0016-01]
- IdEx Emergence call-PALMA
- Universite Paul Sabatier Toulouse-3
- Agence Nationale de la Recherche (ANR) [ANR-12-BSV1-0016] Funding Source: Agence Nationale de la Recherche (ANR)
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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, a, 13-unsaturated hydroxyalkenals), concentration of oxidized LDLs and uptake by scavenger receptors (e.g. CD36, LOX-1, SEA) 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.
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