期刊
CIRCULATION RESEARCH
卷 104, 期 3, 页码 328-U102出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.108.183749
关键词
ER stress; apoptosis; ORP150; oxidized LDL; atherosclerosis
资金
- Institut National de la Sante'et de la Recherche Medicale, L'Agence Nationale de Recherches [ANR-05-PCOD-019-01]
- Universite ' Paul Sabatier, Fondation Coeur et Arteres [FCA-06T6]
- Fondation pour la Recherche Medicale [DCV2007040927]
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 Ire1 alpha and PERK, nuclear translocation of ATF6) and of their subsequent pathways ( eukaryotic initiation factor 2 alpha 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-Ire1 alpha, 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-Ire1 alpha, KDEL, and ORP were faint and more diffuse in intimal hyperplasia. ER stress takes part in the apoptotic effect of oxLDLs, through the Ire1 alpha/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. ( Circ Res. 2009; 104: 328-336.)
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