Different signaling pathways induce apoptosis in endothelial cells and cardiac myocytes during ischemia/reperfusion injury.
Apoptosis contributes, with necrosis, to the cardiac cell loss after ischemia/reperfusion injury. The apoptotic cascade is initiated either by mitochondrial damage and activation of caspase-9 or by death receptor ligation and activation of caspase-8. In the present study, performed in the isolated rat heart exposed either to ischemia alone or ischemia followed by reperfusion, cleavage of caspase-9 was observed primarily in endothelial cells. Conversely, caspase-8 cleavage was only found in cardiomyocytes, where it progressively increased throughout reperfusion. Addition of a specific caspase-9 inhibitor to the perfusate before ischemia prevented endothelial apoptosis, whereas preischemic infusion of a specific caspase-8 inhibitor affected only myocyte apoptosis. Additionally, caspase-8-mediated BID processing was observed only during reperfusion. Production of tBID then sustains mitochondrial injury and perpetuates caspase-9 activation.
Scarabelli
Tiziano M
TM
Medical Molecular Biology Unit, Institute of Child Health, University College London, UK. tscarabelli@hotmail.com
Stephanou
Anastasis
A
Pasini
Evasio
E
Comini
Laura
L
Raddino
Riccardo
R
Knight
Richard A
RA
Latchman
David S
DS
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D003326:Coronary Circulation; D004730:Endothelium, Vascular / Q000473:pathology*; D066298:In Vitro Techniques; D015428:Myocardial Reperfusion Injury / Q000473:pathology* / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology*; D009928:Organ Specificity; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*
D051023:BH3 Interacting Domain Death Agonist Protein; C494816:Bid protein, rat; D002352:Carrier Proteins; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases