ER stress is associated with reduced ABCA-1 protein levels in macrophages treated with advanced glycated albumin - Reversal by a chemical chaperone

Autor(es)

Castilho, Gabriela ^[1] ; Okuda, Ligia S. ^[1] ; Pinto, Raphael S. ^[1] ; Iborra, Rodgiro T. ^[1] ; Nakandakare, Edna R. ^[1] ; Santos, Celio X. ^[2] ; Laurindo, Francisco R. ^[2] ; Passarelli, Marisa ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Med Sci, Lipids Lab LIM 10, BR-01246000 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med Sci, Vasc Biol Lab, Inst Heart, BR-01246000 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY; v. 44, n. 7, p. 1078-1086, JUL 2012.
• Citações Web of Science: 18

Resumo

ATP-binding cassette transporter A1 mediates the export of excess cholesterol from macrophages, contributing to the prevention of atherosclerosis. Advanced glycated albumin (AGE-alb) is prevalent in diabetes mellitus and is associated with the development of atherosclerosis. Independently of changes in ABCA-1 mRNA levels, AGE-alb induces oxidative stress and reduces ABCA-1 protein levels, which leads to macrophage lipid accumulation. These metabolic conditions are known to elicit endoplasmic reticulum (ER) stress. We sought to determine if AGE-alb induces ER stress and unfolded protein response (UPR) in macrophages and how disturbances to the ER could affect ABCA-1 content and cholesterol efflux in macrophages. AGE-alb induced a time-dependent increase in ER stress and UPR markers. ABCA-1 content and cellular cholesterol efflux were reduced by 33% and 47%, respectively, in macrophages treated with AGE-alb, and both were restored by treatment with 4-phenyl butyric acid (a chemical chaperone that alleviates ER stress), but not MG132 (a proteasome inhibitor). Tunicamycin, a classical ER stress inductor, also impaired ABCA-1 expression and cholesterol efflux (showing a decrease of 61% and 82%, respectively), confirming the deleterious effect of ER stress in macrophage cholesterol accumulation. Glycoxidation induces macrophage ER stress, which relates to the reduction in ABCA-1 and in reverse cholesterol transport, endorsing the adverse effect of macrophage ER stress in atherosclerosis. Thus, chemical chaperones that alleviate ER stress may represent a useful tool for the prevention and treatment of atherosclerosis in diabetes. (C) 2012 Elsevier Ltd. All rights reserved. (AU)

• Processo FAPESP: 09/53869-9 - Influência da modificação da albumina no diabete melito sobre a expressão diferencial de genes e o fluxo de lípides em macrófagos
• Beneficiário: Marisa Passarelli
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 10/50108-4 - Glicoxidação intracelular e estresse do retículo endoplasmático: efeito potenciais sobre os transportadores ABCA-1 e sobre o fluxo de lípides em macrófagos
• Beneficiário: Gabriela Castilho
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 10/50147-0 - Albumina modificada por glicação avançada sensibiliza macrófagos a inflamação prejudicando o transporte reverso de colesterol e a atividade anti-inflamatória da HDL
• Beneficiário: Ligia Shimabukuro Okuda
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 09/54688-8 - Estresse glicoxidativo e fluxo de lípides em macrófagos: papel dos inibidores de glicação avançada
• Beneficiário: Raphael de Souza Pinto
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto