Dual role of oxidized LDL on the NF-kappaB signaling pathway.
Atherosclerosis is a slowly evolutive age-linked disease of large arteries, characterized by a local lipid deposition associated with a chronic inflammatory response, leading potentially to acute plaque rupture, thrombosis and ischemic heart disease. Atherogenesis is a complex sequence of events associating first expression of adhesion molecules, recruitment of mononuclear cells to the endothelium, local activation of leukocytes and inflammation, lipid accumulation and foam cell formation. Low density lipoproteins (LDLs) become atherogenic after undergoing oxidation by vascular cells, that transform them into highly bioreactive oxidized LDL (oxidized LDLs). Oxidized LDLs are involved in foam cell formation, and trigger proatherogenic events such as overexpression of adhesion molecules, chemoattractant agents growth factors and cytokines involved in the inflammatory process, cell proliferation and apoptosis. Moreover, this toxic effect of oxidized LDLs plays probably a role in plaque erosion/rupture and subsequent atherothrombosis. Several biological effects of oxidized LDLs are mediated through changes in the activity of transcription factors and subsequently in gene expression. Oxidized LDLs exert a biphasic effect on the redox-sensitive transcription factor NF-kappaB, which can be activated thereby up-regulating proinflammatory gene expression, such as adhesion molecules, tissue factor, scavenger receptor LOX-1. On the other hand, higher concentrations of oxidized LDLs may inhibit NF-kappaB activation triggered by inflammatory agents such as LPS, and may thereby exert an immunosuppressive effect. This review is an attempt to clarify the mechanism by which oxidized LDLs may up- or down-regulate NF-kappaB, the role of NF-kappaB activation (or inhibition), and the consequences of the oxidized LDLs-mediated NF-kappaB dysregulation and their potential involvement in atherosclerosis.
Robbesyn
Fanny
F
INSERM U-466, CHU Rangueil, 31403 Toulouse, Cedex 4, France.
Salvayre
Robert
R
Negre-Salvayre
Anne
A
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D008077:Lipoproteins, LDL; D016328:NF-kappa B; C099252:oxidized low density lipoprotein