title: Activation of the mitochondrial ATP-sensitive K+ channel reduces apoptosis of spleen mononuclear cells induced by hyperlipidemia.
abstract: BACKGROUND
  We have previously demonstrated that increased rates of superoxide generation by extra-mitochondrial 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 mitoK(ATP) 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.
authors.affiliation: Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil.
authors.forename: Luciane C
authors.initials: LC
authors.lastname: Alberici
authors.forename: Bruno A
authors.initials: BA
authors.lastname: Paim
authors.forename: Karina G
authors.initials: KG
authors.lastname: Zecchin
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Mirandola
authors.forename: Cezar R
authors.initials: CR
authors.lastname: Pestana
authors.forename: Roger F
authors.initials: RF
authors.lastname: Castilho
authors.forename: Anibal E
authors.initials: AE
authors.lastname: Vercesi
authors.forename: Helena C F
authors.initials: HC
authors.lastname: Oliveira
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010101:Oxygen Consumption; D015221:Potassium Channels / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013481:Superoxides / Q000378:metabolism*
chemical_list: D015221:Potassium Channels; D017382:Reactive Oxygen Species; C117780:mitochondrial K(ATP) channel; D013481:Superoxides; D000255:Adenosine Triphosphate