Activation of the mitochondrial ATP-sensitive K+ channel reduces apoptosis of spleen mononuclear cells induced by hyperlipidemia

Autor(es)

Alberici, Luciane C. ^{[1, 2]} ; Paim, Bruno A. ^[1] ; Zecchin, Karina G. ^[1] ; Mirandola, Sandra R. ^[1] ; Pestana, Cezar R. ^[2] ; Castilho, Roger F. ^[1] ; Vercesi, Anibal E. ^[1] ; Oliveira, Helena C. F. ^[3]

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas UNICAMP, Fac Ciencias Med, Dept Patol Clin, Campinas, SP - Brazil

^[2] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Fis & Quim, Ribeirao Preto, SP - Brazil

^[3] Univ Estadual Campinas UNICAMP, Inst Biol, Dept Biol Estrutural & Func, Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: LIPIDS IN HEALTH AND DISEASE; v. 12, JUN 14 2013.
• Citações Web of Science: 7

Resumo

Background: We have previously demonstrated that increased rates of superoxide generation by extramitochondrial enzymes induce the activation of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) in the livers of hypertriglyceridemic (HTG) mice. The resulting mild uncoupling mediated by mitoK(ATP) protects mitochondria against oxidative damage. In this study, we investigate whether immune cells from HTG mice also present increased mitoK(ATP) activity and evaluate the influence of this trait on cell redox state and viability. Methods: Oxygen consumption (Clark-type electrode), reactive oxygen species production (dihydroethidium and H2-DCF-DA probes) and cell death (annexin V, cytocrome c release and Trypan blue exclusion) were determined in spleen mononuclear cells. Results: HTG mice mononuclear cells displayed increased mitoK(ATP) activity, as evidenced by higher resting respiration rates that were sensitive to mitoK(ATP) antagonists. Whole cell superoxide production and apoptosis rates were increased in HTG cells. Inhibition of mitoK(ATP) further increased the production of reactive oxygen species and apoptosis in these cells. Incubation with HTG serum induced apoptosis more strongly in WT cells than in HTG mononuclear cells. Cytochrome c release into the cytosol and caspase 8 activity were both increased in HTG cells, indicating that cell death signaling starts upstream of the mitochondria but does involve this organelle. Accordingly, a reduced number of blood circulating lymphocytes was found in HTG mice. Conclusions: These results demonstrate that spleen mononuclear cells from hyperlipidemic mice have more active mitoKATP channels, which downregulate mitochondrial superoxide generation. The increased apoptosis rate observed in these cells is exacerbated by closing the mitoK(ATP) channels. Thus, mitoK(ATP) opening acts as a protective mechanism that reduces cell death induced by hyperlipidemia. (AU)

• Processo FAPESP: 06/59786-0 - Metabolismo energético, homeostase intracelular de CA2+ e estresse oxidativo mitocondrial na morte celular
• Beneficiário: Aníbal Eugênio Vercesi
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 06/53705-8 - Funcao do canal de k+, sensivel a atp, no controle da producao mitocondrial de oxigenio reativo: estudos em camundongos geneticamente hipertrigliceridemicos.
• Beneficiário: Luciane Carla Alberici
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 11/50400-0 - Metabolismo energético, estado redox e funcionalidade mitocondrial na morte celular e em desordens cardiometabólicas e neurodegenerativas
• Beneficiário: Aníbal Eugênio Vercesi
• Modalidade de apoio: Auxílio à Pesquisa - Temático