title: Regulation of Mn-superoxide dismutase activity and neuroprotection by STAT3 in mice after cerebral ischemia.
abstract: Cerebral ischemia and reperfusion increase superoxide anions (O(2)(*-)) in brain mitochondria. Manganese superoxide dismutase (Mn-SOD; SOD2), a primary mitochondrial antioxidant enzyme, scavenges superoxide radicals and its overexpression provides neuroprotection. However, the regulatory mechanism of Mn-SOD expression during cerebral ischemia and reperfusion is still unclear. In this study, we identified the signal transducer and activator of transcription 3 (STAT3) as a transcription factor of the mouse Mn-SOD gene, and elucidated the mechanism of O(2)(*-) overproduction after transient focal cerebral ischemia (tFCI). We found that Mn-SOD expression is significantly reduced by reperfusion in the cerebral ischemic brain. We also found that activated STAT3 is usually recruited into the mouse Mn-SOD promoter and upregulates transcription of the mouse Mn-SOD gene in the normal brain. However, at early postreperfusion periods after tFCI, STAT3 was rapidly downregulated, and its recruitment into the Mn-SOD promoter was completely blocked. In addition, transcriptional activity of the mouse Mn-SOD gene was significantly reduced by STAT3 inhibition in primary cortical neurons. Moreover, we found that STAT3 deactivated by reperfusion induces accumulation of O(2)(*-) in mitochondria. The loss of STAT3 activity induced neuronal cell death by reducing Mn-SOD expression. Using SOD2-/+ heterozygous knock-out mice, we found that Mn-SOD is a direct target of STAT3 in reperfusion-induced neuronal cell death. Our study demonstrates that STAT3 is a novel transcription factor of the mouse Mn-SOD gene and plays a crucial role as a neuroprotectant in regulating levels of reactive oxygen species in the mouse brain.
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Joo Eun
authors.initials: JE
authors.lastname: Jung
authors.forename: Gab Seok
authors.initials: GS
authors.lastname: Kim
authors.forename: Purnima
authors.initials: P
authors.lastname: Narasimhan
authors.forename: Yun Seon
authors.initials: YS
authors.lastname: Song
authors.forename: Pak H
authors.initials: PH
authors.lastname: Chan
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D002545:Brain Ischemia / Q000150:complications / Q000517:prevention & control*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation / Q000379:methods; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004622:Embryo, Mammalian; D005947:Glucose / Q000172:deficiency; D006801:Humans; D000860:Hypoxia; D015850:Interleukin-6 / Q000627:therapeutic use; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000494:pharmacology; D015424:Reperfusion; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000172:deficiency / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D020032:Tyrphostins / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects; D000099156:Superoxide Dismutase 2
chemical_list: D045304:Cytochromes c; D005947:Glucose; D015850:Interleukin-6; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D013482:Superoxide Dismutase; D020032:Tyrphostins; D000099156:Superoxide Dismutase 2; C494087:Stat3 protein, mouse; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide