title: STAT-dependent upregulation of 12/15-lipoxygenase contributes to neuronal injury after stroke.
abstract: Oxidative stress is a major brain injury mechanism after ischemic stroke. 12/15-lipoxygenase (12/15-LOX) is a key mediator of oxidative stress, contributing to neuronal cell death and vascular leakage. Nonetheless, the mechanism leading to its upregulation is currently unknown. We show here that Signal Transducers and Activators of Transcription (STATs), specifically STAT6 and possibly STAT1, increase transcription of 12/15-LOX in neuronal cells. Both p-STAT6 and -1 bound to specific STAT binding sites in the mouse 12/15-LOX promoter. Small interfering RNA (siRNA) knockdown showed STAT6 to be the dominant regulator, reducing 12/15-LOX promoter activation and cell death in oxidatively stressed HT22 cells. STAT6 siRNA efficiently prevented the increase of 12/15-LOX in murine primary neurons, both after induction of oxidative stress and after oxygen-glucose deprivation. Early activation of STAT6 and STAT1 in mice was consistent with a role in regulating 12/15-LOX in focal ischemia. Brains of human stroke patients showed increased p-STAT6 and p-STAT1 in the peri-infarct region, along with 12/15-LOX and markers of apoptosis. These results link STAT6 and STAT1 to the 12/15-LOX damage pathway and suggest disregulation of STAT-dependent transcription as injury mechanism in stroke. Selectively targeting STATs may thus be a novel therapeutic approach to reducing brain injury after a stroke.
authors.affiliation: Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Joo Eun
authors.initials: JE
authors.lastname: Jung
authors.affiliation: Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Hulya
authors.initials: H
authors.lastname: Karatas
authors.affiliation: Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Ege University, Bornova, Izmir, Turkey.|Biruni University, Faculty of Pharmacy, Istanbul, Turkey.
authors.forename: Ayfer
authors.initials: A
authors.lastname: Yalcin
authors.affiliation: Laboratorio de Investigación Neurovascular Hospital Vall d'Hebron, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
authors.affiliation: Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.affiliation: Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: van Leyen
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis*; D005260:Female; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000172:deficiency; D006801:Humans; D002534:Hypoxia, Brain / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009474:Neurons / Q000473:pathology*; D018384:Oxidative Stress; D034741:RNA, Small Interfering; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology; D050791:STAT Transcription Factors / Q000378:metabolism*; D020521:Stroke / Q000201:enzymology* / Q000473:pathology; D015854:Up-Regulation
chemical_list: D034741:RNA, Small Interfering; D050791:STAT Transcription Factors; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D005947:Glucose