期刊
JOURNAL OF LIPID RESEARCH
卷 55, 期 11, 页码 2320-2333出版社
ELSEVIER
DOI: 10.1194/jlr.M051094
关键词
endoplasmic reticulum; macrophages; atherosclerosis; signal transduction; protein kinases; PERK; endoplasmic reticulum stress
资金
- Canadian Institutes for Health Research
- Heart and Stroke Foundation of Ontario [000031]
- Canadian Institutes for Health Research [MOP62910, MOP133612]
Evidence suggests a causative role for endoplasmic reticulum (ER) stress in the development of atherosclerosis. This study investigated the potential role of glycogen synthase kinase (GSK)-3 alpha/beta in proatherogenic ER stress signaling. Thp1-derived macrophages were treated with the ER stress-inducing agents, glucosamine, thapsigargin, or palmitate. Using small-molecule inhibitors of specific unfolded protein response (UPR) signaling pathways, we found that protein kinase R-like ER kinase (PERK), but not inositol requiring enzyme 1 or activating transcription factor 6, is required for the activation of GSK3 alpha/beta by ER stress. GSK3 alpha/beta inhibition or siRNA-directed knockdown attenuated ER stress-induced expression of distal components of the PERK pathway. Macrophage foam cells within atherosclerotic plaques and isolated macrophages from ApoE(-/-) mice fed a diet supplemented with the GSK3 alpha/beta inhibitor valproate had reduced levels of C/EBP homologous protein (CHOP). GSK3 alpha/beta inhibition blocked ER stress-induced lipid accumulation and the upregulation of genes associated with lipid metabolism. In primary mouse macrophages, PERK inhibition blocked ER stress-induced lipid accumulation, whereas constitutively active S9A-GSK3 beta promoted foam cell formation and CHOP expression, even in cells treated with a PERK inhibitor. These findings suggest that ER stress-PERK-GSK3 alpha/beta signaling promotes proatherogenic macrophage lipid accumulation.
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