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

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 296; no. 4; p. H1164
• Main Authors: Radhakrishnan, Jeejabai, Ayoub, Iyad M, Gazmuri, Raúl J
• Format: Journal Article
• Language: English
• Published: United States 01-04-2009
• Subjects: Animals; Anti-Arrhythmia Agents - pharmacology; Apoptosis - physiology; Caspase 3 - metabolism; Caspase Inhibitors; Disease Models, Animal; DNA Fragmentation; Guanidines - pharmacology; Heart - physiopathology; Heart Massage; Male; Myocardial Contraction - drug effects; Myocardial Contraction - physiology; Myocardium - metabolism; Myocardium - pathology; Oligopeptides - pharmacology; Rats; Rats, Sprague-Dawley; Resuscitation - methods; Sodium-Hydrogen Exchangers - antagonists & inhibitors; Sodium-Hydrogen Exchangers - metabolism; Sulfones - pharmacology; Ventricular Dysfunction, Left - metabolism; Ventricular Dysfunction, Left - physiopathology; Ventricular Fibrillation - metabolism; Ventricular Fibrillation - physiopathology
• ISSN: 0363-6135
• DOI: 10.1152/ajpheart.00338.2008

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.