Inhibition of caspase-3 improves contractile recovery of stunned myocardium, independent of apoptosis-inhibitory effects

OBJECTIVES The aim of this study was to investigate whether the caspase-3 i nhibitor Ac-DEVD-CHO functionally improves stunned myocardium. BACKGROUND Degradation of troponin I contributes to the pathogenesis of myo cardial stunning, whereas the role of apoptosis is unknown. Caspase-3 is an essential apoptotic protease that is specifically inhibited by Ac-DEVD-CHO . METHODS Isolated working hearts of rats were exposed to 30 min of low-flow ischemia, followed by 30 min of reperfusion. Ac-DEVD-CHO (0.1 to 1 mu mol/l ) was added 15 min before ischemia/reperfusion or 5 min before reperfusion. Cardiac output, external heart power, left ventricular (LV) developing pre ssure and contractility (dp/dt(max)) were measured. Apoptosis was assessed by TUNEL staining and internucleosomal deoxyribonucleic acid fragmentation. Caspase-3 processing and troponin I cleavage were determined by immunoblot ting. Caspase-3 activity was measured using a fluorogenic substrate. RESULTS The addition of Ac-DEVD-CHO before ischemia/reperfusion or before r eperfusion dose-dependently and significantly (p < 0.05) improved post-isch emic recovery of cardiac output, external heart power, LV developing pressu re and dp/dt(max), compared with the vehicle (0.01% dimethyl sulfoxide). Ac -DEVD-CHO was similarly effective when given before reperfusion. Ac-DEVD-CH O blocked ischemia/reperfusion-induced caspase-3 activation, but cardiomyoc yte apoptosis was unaffected. Troponin I cleavage was not inhibited by Ac-D EVD-CHO. CONCLUSIONS Caspase-3 is activated in stunned myocardium. Inhibition of cas pase-3 by Ac-DEVD-CHO significantly improves post-ischemic contractile reco very of stunned myocardium, even when given after the onset of ischemia. Th e mechanism(s) of protection by Ac-DEVD-CHO appear to be independent of apo ptosis. Inhibition of caspase-3 is a novel therapeutic strategy to improve functional recovery of stunned myocardium. (J Am Coll Cardiol 2001;38: 2063 -70) (C) 2001 by the American College of Cardiology.