NADPH oxidase-derived ROS: key modulators of heme-induced mitochondrial stability in human neutrophils |
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Authors: | Arruda Maria Augusta Barcellos-de-Souza Pedro Sampaio André Luiz Franco Rossi Adriano G Graça-Souza Aurélio V Barja-Fidalgo Christina |
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Affiliation: | Departamento de Farmacologia, Instituto de Biologia, Universidade do Estado do Rio de Janeiro, Av. 28 de setembro 87-Vila Izabel, Rio de Janeiro, RJ, 20551-030 Brazil. |
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Abstract: | Heme is a proinflammatory molecule able to cause a profound delay of constitutive apoptosis of human neutrophils, an effect that likely contributes to chronic inflammation associated with hemolytic diseases. Herein we show that heme-induced delay of neutrophil apoptosis correlates with the prevention of mitochondrial potential (Deltapsi(m)) dissipation by a mechanism dependent on NADPH oxidase (NADPHox)-generated reactive oxygen species (ROS) and NF-kappaB. Deltapsi(m) maintenance is accompanied by inhibition of Bax insertion into mitochondria and by a decrease in the Bad/Bcl-X(L) ratio. Heme induces Bad degradation in a completely ROS-dependent manner, as well as Bcl-X(L) synthesis, a phenomenon that also requires NF-kappaB activation. These data indicate that heme-induced preservation of mitochondrial integrity is a critical checkpoint controlled by NADPH oxidase generated-ROS and redox-sensitive NF-kappaB activation. |
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Keywords: | NADPHox, NADPH oxidase ROS, reactive oxygen species Δψm, mitochondria transmembrane potential MAPK, mitogen-activated protein kinase ERK, extracellular signal-regulated protein kinase PI3K, phosphatidylinositol 3 kinase NF, nuclear factor PKC, protein kinase C IL, interleukin GM-CSF, granulocyte macrophage colony stimulation factor DPI, diphenyleneiodonium PDTC, pyrrolidine dithiocarbamate COx, cytochrome c oxidase subunit IV PICD, phagocytosis-induced cell death PMSF, phenylmethylsulfonyl fluoride |
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