Regulation of Mn-superoxide dismutase activity and neuroprotection by STAT3 in mice after cerebral ischemia.
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.
Jung
Joo Eun
JE
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305, USA.
Kim
Gab Seok
GS
Narasimhan
Purnima
P
Song
Yun Seon
YS
Chan
Pak H
PH
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
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