Activation of caspase-3 may not contribute to postresuscitation myocardial dysfunction.

Abstract

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.

• Authors: Jeejabai Radhakrishnan, Iyad M Ayoub, Raúl J Gazmuri
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 296 Issue 4 Pg. H1164-74 (Apr 2009) ISSN: 0363-6135 [Print] United States
• PMID: 19234092 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• Caspase Inhibitors
• Guanidines
• Oligopeptides
• Sodium-Hydrogen Exchangers
• Sulfones
• benzyloxycarbonyl aspartyl-glutamyl-valyl-aspartyl-chloromethyl ketone
• growth factor-activatable Na-H exchanger NHE-1
• cariporide
• Caspase 3

Topics

• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Apoptosis (physiology)
• Caspase 3 (metabolism)
• Caspase Inhibitors
• DNA Fragmentation
• Disease Models, Animal
• Guanidines (pharmacology)
• Heart (physiopathology)
• Heart Massage
• Male
• Myocardial Contraction (drug effects, physiology)
• Myocardium (metabolism, pathology)
• Oligopeptides (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Resuscitation (methods)
• Sodium-Hydrogen Exchangers (antagonists & inhibitors, metabolism)
• Sulfones (pharmacology)
• Ventricular Dysfunction, Left (metabolism, physiopathology)
• Ventricular Fibrillation (metabolism, physiopathology)