title: Hypoxia in high glucose followed by reoxygenation in normal glucose reduces the viability of cortical astrocytes through increased permeability of connexin 43 hemichannels.
abstract: Brain ischemia causes more extensive injury in hyperglycemic than normoglycemic subjects, and the increased damage is to astroglia as well as neurons. In the present work, we found that in cortical astrocytes from rat or mouse, reoxygenation after hypoxia in a medium mimicking interstitial fluid during ischemia increases hemichannel activity and decreases cell-cell communication via gap junctions as indicated by dye uptake and dye coupling, respectively. These effects were potentiated by high glucose during the hypoxia in a concentration-dependent manner (and by zero glucose) and were not observed in connexin 43(-/-) astrocytes. The responses were transient and persistent after short and long periods of hypoxia, respectively. The persistent responses were associated with a progressive reduction in cell viability that was prevented by La(3+) or peptides that block connexin 43 (Cx43) hemichannels or by inhibition of p38 MAP kinase prior to hypoxia-reoxygenation but not by treatments that block pannexin hemichannels. Block of Cx43 hemichannels did not affect the reduction in gap junction mediated dye coupling observed during reoxygenation. Cx43 hemichannels may be a novel therapeutic target to reduce cell death following stroke, particularly in hyperglycemic conditions.
authors.affiliation: Departamento de Ciencias Fisiológicas, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile. jaorella@uc.cl
authors.forename: Juan A
authors.initials: JA
authors.lastname: Orellana
authors.forename: Diego E
authors.initials: DE
authors.lastname: Hernández
authors.forename: Pascal
authors.initials: P
authors.lastname: Ezan
authors.forename: Victoria
authors.initials: V
authors.lastname: Velarde
authors.forename: Michael V L
authors.initials: MV
authors.lastname: Bennett
authors.forename: Christian
authors.initials: C
authors.lastname: Giaume
authors.forename: Juan C
authors.initials: JC
authors.lastname: Sáez
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism* / Q000503:physiopathology; D018031:Connexin 43 / Q000187:drug effects / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism* / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism* / Q000503:physiopathology; D002534:Hypoxia, Brain / Q000378:metabolism* / Q000503:physiopathology; D007811:Lanthanum / Q000494:pharmacology; D051379:Mice; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology
chemical_list: D018031:Connexin 43; D005456:Fluorescent Dyes; D010455:Peptides; D007811:Lanthanum; D005947:Glucose; D010100:Oxygen
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