title: SOD3 decreases ischemic injury derived apoptosis through phosphorylation of Erk1/2, Akt, and FoxO3a.
abstract: BACKGROUND
  Extracellular superoxide dismutase (SOD3), which dismutates superoxide anion to hydrogen peroxide, has been shown to reduce the free radical stress derived apoptosis in tissue injuries. Since both superoxide anion and hydrogen peroxide have a marked impact on signal transduction pathways and could potentially explain a number of apoptosis and survival -related phenomena in different pathological conditions, we clarified the impact of SOD3 on Akt and Erk1/2 cell survival pathways in rat hind limb injury model.
  
  
  RESULTS
  Based on our data, the hind limb ischemic rats treated with virally delivered sod3 have milder injury and less apoptosis than control animals that could be due to parallel activation of pro-proliferative and anti-apoptotic Erk1/2 and Akt pathways. The common downstream factor of both signaling pathways, the apoptosis related forkhead box protein O3a (FoxO3a), was phosphorylated and translocated to the cytoplasm in sod3 treated tissues and cell line. Additionally, we obtained increased mRNA production of elk-1, ets-1, and microRNA 21 (miR-21), whereas synthesis of bim mRNA was decreased in sod3 overexpressing tissues. We further showed that overexpression of sod3 modulated redox related gene expression by downregulating nox2 and inos when compared to injured control animals.
  
  
  CONCLUSIONS
  The study shows the complexity of SOD3-derived effects on tissue injury recovery that are not limited to the reduction of superoxide anion caused cellular stress but highlights the impact of SOD3 related signal transduction on tissue functions and suggests an important role for SOD3 in attenuating cell stress effects in different pathological conditions.
authors: University of Turku, Medicity Research Laboratory, Turku, Finland.
authors: Lilja E
authors: LE
authors: Laatikainen
authors: Mariarosaria
authors: M
authors: Incoronato
authors: Maria Domenica
authors: MD
authors: Castellone
authors: Juha P
authors: JP
authors: Laurila
authors: Massimo
authors: M
authors: Santoro
authors: Mikko O
authors: MO
authors: Laukkanen
mesh_terms: D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D007511:Ischemia / Q000201:enzymology* / Q000473:pathology*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C499089:Sod3 protein, rat; D013482:Superoxide Dismutase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3