Oxidized low density lipoprotein increases RANKL level in human vascular cells. Involvement of oxidative stress.
Receptor Activator of NFκB Ligand (RANKL) and its decoy receptor osteoprotegerin (OPG) have been shown to play a role not only in bone remodeling but also in inflammation, arterial calcification and atherosclerotic plaque rupture. In human smooth muscle cells, Cu(2+)-oxidized LDL (CuLDL) 10-50 μg/ml increased reactive oxygen species (ROS) and RANKL level in a dose-dependent manner, whereas OPG level was not affected. The lipid extract of CuLDL reproduced the effects of the whole particle. Vivit, an inhibitor of the transcription factor NFAT, reduced the CuLDL-induced increase in RANKL, whereas PKA and NFκB inhibitors were ineffective. LDL oxidized by myeloperoxidase (MPO-LDL), or other pro-oxidant conditions such as ultraviolet A (UVA) irradiation, incubation with H2O2 or with buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, also induced an oxidative stress and enhanced RANKL level. The increase in RANKL in pro-oxidant conditions was also observed in fibroblasts and endothelial cells. Since RANKL is involved in myocardial inflammation, vascular calcification and plaque rupture, this study highlights a new mechanism whereby OxLDL might, by generation of an oxidative stress, exert a deleterious effect on different cell types of the arterial wall.
Biochemistry Laboratory, South Hospital University, René Laennec Avenue, Amiens 80000, France. Electronic address: maziere.cecile@chu-amiens.fr.
Cécile
C
Mazière
Valéry
V
Salle
Cathy
C
Gomila
Jean-Claude
JC
Mazière
D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000494:pharmacology; D053244:Osteoprotegerin / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism*
D008077:Lipoproteins, LDL; D050778:NFATC Transcription Factors; D009842:Oligopeptides; D053244:Osteoprotegerin; D053245:RANK Ligand; C121611:VIVIT peptide; C099252:oxidized low density lipoprotein; D009195:Peroxidase
BSO; Cu(2+)-oxidized LDL; CuLDL; H(2)O(2); HCASMC; LDL; MPO-LDL; Myocardial inflammation; NFAT; OPG; OxLDL; Oxidative stress; Oxidized LDL; RANKL; ROS; Vascular calcification; buthionine sulfoximine; human coronary artery smooth muscle cells; hydrogen peroxide; low density lipoprotein; myeloperoxidase-oxidized LDL; nuclear factor of activated T cells; osteoprotegerin; oxidized LDL; reactive oxygen species; receptor activator of NFkappaB ligand