Activation of caspase-3 may not contribute to postresuscitation myocardial dysfunction.
We have previously reported that postresuscitation myocardial dysfunction is accompanied by the release of cytochrome c and caspase-3 activation. We now investigated the role of caspase-3 activation by examining whether such process prompts apoptotic DNA fragmentation, whether caspase-3 inhibition attenuates myocardial dysfunction, and whether myocardial protective effects of sodium-hydrogen exchanger isoform-1 (NHE-1) inhibition involve caspase-3 inhibition using a rat model of ventricular fibrillation (VF) of closed-chest resuscitation. Resuscitation after 4 or 8 min of untreated VF caused significant reductions in left ventricular stroke work index averaging 23% of sham control rats at 4 h postresuscitation. Left ventricular dysfunction was accompanied by increases in cytosolic cytochrome c, decreases in pro- and cleaved caspase-9 fragments, increases in 17-kDa caspase-3 fragments, and increases in caspase-3 activity indicating the activation of the mitochondrial apoptotic pathway but without evidence of apoptotic DNA fragmentation. In addition, levels of heat shock protein 70 were increased and levels of X-linked inhibitor of apoptosis protein and alphabeta-crystallin were preserved, all of which can exert antiapoptotic effects. In a separate series, the caspase-3 inhibitor z-Asp-Glu-Val-Asp chloromethyl ketone given before the induction of VF failed to prevent postresuscitation myocardial dysfunction despite reductions in caspase-3 activity (2.3 +/- 0.5 vs. 1.3 +/- 0.5 pmol fluorophore AFC released.mg protein(-1).min-1; P < 0.03). Treatment with the NHE-1 inhibitor cariporide had no effect on caspase-3 activity. Accordingly, in this rat model of VF and severe postresuscitation myocardial dysfunction, activation of caspase-3 did not lead to DNA fragmentation or contribute to myocardial dysfunction. Concomitant activation of intrinsic antiapoptotic mechanisms could play a protective role downstream to caspase-3 activation.
Radhakrishnan
Jeejabai
J
Medical Service (111F North Chicago VA Medical Center, 3001 Green Bay Road, North Chicago, IL 60064, USA.
Ayoub
Iyad M
IM
Gazmuri
Raúl J
RJ
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D006146:Guanidines / Q000494:pharmacology; D006321:Heart / Q000503:physiopathology*; D006336:Heart Massage; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation / Q000379:methods*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000503:physiopathology*; D014693:Ventricular Fibrillation / Q000378:metabolism / Q000503:physiopathology*
D000889:Anti-Arrhythmia Agents; D061945:Caspase Inhibitors; D006146:Guanidines; D009842:Oligopeptides; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C120992:benzyloxycarbonyl aspartyl-glutamyl-valyl-aspartyl-chloromethyl ketone; C069139:growth factor-activatable Na-H exchanger NHE-1; C093373:cariporide; D053148:Caspase 3