Hypoxia-mediated induction of heme oxygenase type I and carbon monoxide release from astrocytes protects nearby cerebral neurons from hypoxia-mediated apoptosis.
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.
Imuta
Naohiko
N
Department of Medicine, Seiwa Hospital, Osaka, Japan.
Hori
Osamu
O
Kitao
Yasuko
Y
Tabata
Yoshiyuki
Y
Yoshimoto
Tanihiro
T
Matsuyama
Tomohiro
T
Ogawa
Satoshi
S
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
D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D010100:Oxygen