Evidence for caspase effects on release of cytochrome c and AIF in a model of ischemia in cortical neurons.
Neuronal apoptosis following ischemia can be mediated by a caspase-dependent pathway, which involves the mitochondrial release of cytochrome c that initiates a cascade of caspase activation. In addition, there is a caspase-independent pathway, which is mediated by the release of apoptosis-inducing factor (AIF). Using caspase inhibitor gene therapy, we investigated the roles of caspases on the mitochondrial release of cyt c and the release of AIF. Specifically, we used herpes simplex virus-1 amplicon vectors to ectopically express a viral caspase inhibitor (crmA or p35) in mixed cortical cultures exposed to oxygen/glucose deprivation. Overexpression of either crmA or p35 (but not the caspase-3 inhibitor DEVD) inhibited the release of AIF; this suggests that there can be cross-talk between the caspase-dependent and the ostensibly caspase-independent pathway. In addition, both crmA overexpression and DEVD inhibited cyt c release, suggesting a positive feedback loop involving activated caspases stimulating cyt c release.
Singh
Maneesh H
MH
Department of Biological Sciences, and Neurology and Neurological Sciences, Stanford University, 371 Serra Street, Stanford, CA 94305, USA.
Brooke
Sheila M
SM
Zemlyak
Ilona
I
Sapolsky
Robert M
RM
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D005947:Glucose / Q000172:deficiency; D018259:Herpesvirus 1, Human / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
C494831:Aifm1 protein, rat; D051033:Apoptosis Inducing Factor; D061945:Caspase Inhibitors; D045304:Cytochromes c; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005947:Glucose