title: Release of mitochondrial apoptogenic factors and cell death are mediated by CK2 and NADPH oxidase.
abstract: Activation of the NADPH oxidase subunit, NOX2, and increased oxidative stress are associated with neuronal death after cerebral ischemia and reperfusion. Inhibition of NOX2 by casein kinase 2 (CK2) leads to neuronal survival, but the mechanism is unknown. In this study, we show that in copper/zinc-superoxide dismutase transgenic (SOD1 Tg) mice, degradation of CK2α and CK2α' and dephosphorylation of CK2β against oxidative stress were markedly reduced compared with wild-type (WT) mice that underwent middle cerebral artery occlusion. Inhibition of CK2 pharmacologically or by ischemic reperfusion facilitated accumulation of poly(ADP-ribose) polymers, the translocation of apoptosis-inducing factor (AIF), and cytochrome c release from mitochondria after ischemic injury. The eventual enhancement of CK2 inhibition under ischemic injury strongly increased 8-hydroxy-2'-deoxyguanosine and phosphorylation of H2A.X. Furthermore, CK2 inhibition by tetrabromocinnamic acid (TBCA) in SOD1 Tg and gp91 knockout (KO) mice after ischemia reperfusion induced less release of AIF and cytochrome c than in TBCA-treated WT mice. Inhibition of CK2 in gp91 KO mice subjected to ischemia reperfusion did not increase brain infarction compared with TBCA-treated WT mice. These results strongly suggest that NOX2 activation releases reactive oxygen species after CK2 inhibition, triggering release of apoptogenic factors from mitochondria and inducing DNA damage after ischemic brain injury.
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305-5487, USA.
authors.forename: Gab Seok
authors.initials: GS
authors.lastname: Kim
authors.forename: Joo Eun
authors.initials: JE
authors.lastname: Jung
authors.forename: Purnima
authors.initials: P
authors.lastname: Narasimhan
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakata
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshioka
authors.forename: Yun Seon
authors.initials: YS
authors.lastname: Song
authors.forename: Nobuya
authors.initials: N
authors.lastname: Okami
authors.forename: Pak H
authors.initials: PH
authors.lastname: Chan
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism*; D020520:Brain Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology; D045304:Cytochromes c / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005260:Female; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D000080242:8-Hydroxy-2'-Deoxyguanosine; D051033:Apoptosis Inducing Factor; D047390:Casein Kinase II; D002934:Cinnamates; D045304:Cytochromes c; D003848:Deoxyguanine Nucleotides; D006657:Histones; D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D009419:Nerve Tissue Proteins; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C521293:8-hydroxy-2'-deoxyguanosine 5'-triphosphate; C494830:AIFM1 protein, mouse; C518786:tetrabromocinnamic acid; C000606291:Sod1 protein, mouse; C488842:Cybb protein, mouse; C475961:gamma-H2AX protein, mouse