title: Knockdown of apoptosis signal-regulating kinase 1 affects ischaemia-induced astrocyte activation and glial scar formation.
abstract: Reactive astrocytes play an essential role in determining the tissue response to ischaemia. Formation of a glial scar can block the neuronal outgrowth that is required for restoration of damaged tissue. Therefore, regulation of astrocyte activation is important; however, the mediator of this process has not been fully elucidated. Apoptosis signal-regulating kinase 1 (ASK1) is an early responder to oxidative stress, and plays a pivotal role in the intracellular signalling pathway of apoptosis, inflammation, and differentiation. To confirm whether ASK1 mediates astrocyte activation and leads to glial scar formation after cerebral ischaemia, we conducted in vivo and in vitro experiments. C57BL/6 mice were subjected to occlusion of the middle cerebral artery, and astrocyte cultures were exposed to oxygen-glucose deprivation. After silencing of ASK1 , astrocyte-associated genes were downregulated, as seen with the use of microarrays. The glial fibrillary acidic protein (GFAP) level was decreased, and correlated with the reduction in the ASK1 level. In astrocytes, reduction in the ASK1 level decreased the activity of the p38 pathway, and the levels of transcription factors for GFAP and GFAP transcripts after hypoxia. In the chronic phase, ASK1 depletion reduced glial scar formation and conserved neuronal structure, which may lead to better functional recovery. These data suggest that ASK1 may be an important mediator of ischaemia-induced astrocyte activation and scar formation, and could provide a potential therapeutic target for treatment after ischaemic stroke.
authors.affiliation: Department of Anaesthesiology and Pain Medicine, College of Medicine, Yonsei University, Seoul, Korea.
authors.forename: So Yeong
authors.initials: SY
authors.lastname: Cheon
authors.affiliation: Department of Neurology, College of Medicine, Yonsei University, 50, Yonsei-ro, Seodaemun-gu, 120-752, Seoul, Korea.
authors.forename: Kyoung Joo
authors.initials: KJ
authors.lastname: Cho
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada.
authors.forename: Juhyun
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Neurology, College of Medicine, Yonsei University, 50, Yonsei-ro, Seodaemun-gu, 120-752, Seoul, Korea.
authors.forename: Gyung Whan
authors.initials: GW
authors.lastname: Kim
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002921:Cicatrix / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism* / Q000473:pathology; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse
keywords: apoptosis signal-regulating kinase 1; cerebral ischaemia; glial scar formation; reactive astrocyte; small interfering RNA