title: Hypoxia-mediated induction of heme oxygenase type I and carbon monoxide release from astrocytes protects nearby cerebral neurons from hypoxia-mediated apoptosis.
abstract: To study a putative paracellular protective mechanism of astrocytes for neurons, immunohistochemical analysis was performed in ischemic rat brain, which colocalized with the expression of heme oxygase-1 (HO- 1) in astroglias surrounding dying TUNEL-positive neurons. As an in vitro paradigm for ischemia, cultured astrocytes were exposed to normobaric hypoxia (pO(2) asymptotically equal to 10 torr), which triggered marked increase in the expression of a 33 kDa stress protein, identified as HO-1. Induction of HO-1 message was observed within 4 h of hypoxia and peaked at 12 h, accompanied by an accelerated transcription of HO-1 message. Consistent with the induction of HO-1, a platelet bioassay revealed production of carbon monoxide by reoxygenated astrocytes. The presence of CO in the medium decelerated the hypoxia-mediated apoptotic type of cell death in cultured cerebral neurons via lowering the activity of caspase-3, a key enzyme regulating apoptotic cell death. This protection against apoptosis was likely mediated by CO-mediated increases in intracellular cGMP, because exposure of hypoxic neurons to CO increased intracellular cGMP levels, and addition of cGMP analogue to hypoxic neuronal cultures suppressed caspase-3 activity and promoted neuronal survival. These data describe a potentially important paracellular pathway through which astrocytes may rescue nearby neurons from ischemic death.
authors.affiliation: Department of Medicine, Seiwa Hospital, Osaka, Japan.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Imuta
authors.forename: Osamu
authors.initials: O
authors.lastname: Hori
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kitao
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tabata
authors.forename: Tanihiro
authors.initials: T
authors.lastname: Yoshimoto
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsuyama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000201:enzymology* / Q000378:metabolism; D001921:Brain / Q000166:cytology* / Q000378:metabolism / Q000473:pathology*; D002545:Brain Ischemia / Q000139:chemically induced / Q000201:enzymology*; D002248:Carbon Monoxide / Q000378:metabolism* / Q000502:physiology; D015687:Cell Hypoxia; D002470:Cell Survival; D002478:Cells, Cultured; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008297:Male; D009474:Neurons / Q000201:enzymology* / Q000502:physiology; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D010100:Oxygen