Oxidized low-density lipoproteins trigger endoplasmic reticulum stress in vascular cells: prevention by oxygen-regulated protein 150 expression.
Oxidized low-density lipoproteins (oxLDLs) trigger various biological responses potentially involved in atherogenesis. Disturbing endoplasmic reticulum (ER) function results in ER stress and unfolded protein response, which tends to restore ER homeostasis but switches to apoptosis when ER stress is prolonged. We aimed to investigate whether ER stress is induced by oxLDLs and can be prevented by the ER-associated chaperone ORP150 (150-kDa oxygen-regulated protein). oxLDLs and the lipid oxidation products 7-ketocholesterol and 4-hydroxynonenal induce ER stress in human endothelial cells (HMEC-1), characterized by the activation of ER stress sensors (phosphorylation of Ire1alpha and PERK, nuclear translocation of ATF6) and of their subsequent pathways (eukaryotic initiation factor 2alpha phosphorylation, expression of XBP1/spliced XBP1, CHOP, and KDEL chaperones GRP78, GRP94, ORP150). ER stress was inhibited by the antioxidant N-acetylcysteine. In advanced atherosclerotic lesions, phospho-Ire1alpha, KDEL, and ORP150 staining were localized in lipid-rich areas with 4-hydroxynonenal adducts and CD68-positive macrophagic cells. By comparison, staining for 4-hydroxynonenal, phospho-Ire1alpha, KDEL, and ORP were faint and more diffuse in intimal hyperplasia. ER stress takes part in the apoptotic effect of oxLDLs, through the Ire1alpha/c-Jun N-terminal kinase pathway, as assessed by the protective effect of specific small interfering RNAs and c-Jun N-terminal kinase inhibitor. Forced expression of the chaperone ORP150 reduced both oxLDL-induced ER stress and apoptosis. ER stress markers and ORP150 chaperone are expressed in areas containing oxLDLs in atherosclerotic lesions and are induced by oxLDLs and oxidized lipids in cultured cells. The forced expression of ORP150 highlights its new protective role against oxLDL-induced ER stress and subsequent apoptosis.
Sanson
Marie
M
Institut National de la Santé et de la Recherche Médicale, U-858, Vascular Biology Department, IFR-31, Toulouse, France.
Augé
Nathalie
N
Vindis
Cécile
C
Muller
Carole
C
Bando
Yoshio
Y
Thiers
Jean-Claude
JC
Marachet
Marie-Agnès
MA
Zarkovic
Kamelija
K
Sawa
Yoshiki
Y
Salvayre
Robert
R
Nègre-Salvayre
Anne
A
D000111:Acetylcysteine / Q000494:pharmacology; D000447:Aldehydes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins; D006801:Humans; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007653:Ketocholesterols / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*
D000447:Aldehydes; D015415:Biomarkers; D015853:Cysteine Proteinase Inhibitors; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D018840:HSP70 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D007653:Ketocholesterols; D008077:Lipoproteins, LDL; D011506:Proteins; C099252:oxidized low density lipoprotein; C050087:oxygen-regulated proteins; D048031:JNK Mitogen-Activated Protein Kinases; C027576:4-hydroxy-2-nonenal; C003001:7-ketocholesterol; D010100:Oxygen; D000111:Acetylcysteine