TY - JOUR
T1 - Ischemic Preconditioning
T2 - Neuronal Survival in the Face of Caspase-3 Activation
AU - Tanaka, Hidenobu
AU - Yokota, Hidenori
AU - Jover, Teresa
AU - Cappuccio, Irene
AU - Calderone, Agata
AU - Simionescu, Monica
AU - Bennett, Michael V.L.
AU - Zukin, R. Suzanne
PY - 2004/3/17
Y1 - 2004/3/17
N2 - Apoptosis is an evolutionarily conserved process critical to tissue development and tissue homeostasis in eukaryotic organisms and, when dysregulated, causes inappropriate cell death. Global ischemia is a neuronal insult that induces delayed cell death with many features of apoptosis. Ischemic preconditioning affords robust protection of CA1 neurons against a subsequent severe ischemic challenge. The molecular mechanisms underlying ischemic tolerance are unclear. Here we show that ischemia induces pronounced caspase-3 activity in naive neurons that die and in preconditioned neurons that survive. Preconditioning intervenes downstream of proteolytic processing and activation of caspase-3 (a protease implicated in the execution of apoptosis) and upstream of the caspase-3 target caspase-activated DNase (CAD, a deoxyribonuclease that catalyzes DNA fragmentation) to arrest neuronal death. We further show that global ischemia promotes expression of the pro-survival inhibitor-of-apoptosis (IAP) family member cIAP, but unleashes Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI), a factor that neutralizes the protective actions of IAPs and promotes neuronal death. Preconditioning blocks the mitochondrial release of Smac/DIABLO, but not the ischemia-induced upregulation of IAPs. In the absence of Smac/DIABLO, cIAP halts the caspase death cascade and arrests neuronal death. These findings suggest that preconditioning preserves the integrity of the mitochondrial membrane, enabling neurons to survive in the face of caspase activation.
AB - Apoptosis is an evolutionarily conserved process critical to tissue development and tissue homeostasis in eukaryotic organisms and, when dysregulated, causes inappropriate cell death. Global ischemia is a neuronal insult that induces delayed cell death with many features of apoptosis. Ischemic preconditioning affords robust protection of CA1 neurons against a subsequent severe ischemic challenge. The molecular mechanisms underlying ischemic tolerance are unclear. Here we show that ischemia induces pronounced caspase-3 activity in naive neurons that die and in preconditioned neurons that survive. Preconditioning intervenes downstream of proteolytic processing and activation of caspase-3 (a protease implicated in the execution of apoptosis) and upstream of the caspase-3 target caspase-activated DNase (CAD, a deoxyribonuclease that catalyzes DNA fragmentation) to arrest neuronal death. We further show that global ischemia promotes expression of the pro-survival inhibitor-of-apoptosis (IAP) family member cIAP, but unleashes Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI), a factor that neutralizes the protective actions of IAPs and promotes neuronal death. Preconditioning blocks the mitochondrial release of Smac/DIABLO, but not the ischemia-induced upregulation of IAPs. In the absence of Smac/DIABLO, cIAP halts the caspase death cascade and arrests neuronal death. These findings suggest that preconditioning preserves the integrity of the mitochondrial membrane, enabling neurons to survive in the face of caspase activation.
KW - Apoptosis
KW - Caspase death cascade
KW - DNA fragmentation factor
KW - Ischemic insults
KW - Ischemic preconditioning
KW - Neuronal death
KW - Neuroprotection
KW - Tolerance
UR - http://www.scopus.com/inward/record.url?scp=1642386777&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=1642386777&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.5475-03.2004
DO - 10.1523/JNEUROSCI.5475-03.2004
M3 - Article
C2 - 15028768
AN - SCOPUS:1642386777
SN - 0270-6474
VL - 24
SP - 2750
EP - 2759
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 11
ER -