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EXPERIMENTAL STUDY

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

^a Aventis Pharmaceuticals, Frankfurt, Germany
^b Molecular Cardiology, Department of Medicine IV, Goethe-University, Frankfurt, Germany
^c Department of Pathology, University of Freiburg, Freiburg, Germany

Manuscript received November 7, 2000; revised manuscript received August 10, 2001, accepted August 29, 2001.

^* Reprint requests and correspondence: Dr. Stefanie Dimmeler, Molecular Cardiology Unit, Department of Medicine IV, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
Dimmeler{at}em.uni-frankfurt.de

OBJECTIVES: The aim of this study was to investigate whether the caspase-3 inhibitor Ac-DEVD-CHO functionally improves stunned myocardium.

BACKGROUND: Degradation of troponin I contributes to the pathogenesis of myocardial 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 µmol/l) was added 15 min before ischemia/reperfusion or 5 min before reperfusion. Cardiac output, external heart power, left ventricular (LV) developing pressure 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 immunoblotting. Caspase-3 activity was measured using a fluorogenic substrate.

RESULTS: The addition of Ac-DEVD-CHO before ischemia/reperfusion or before reperfusion dose-dependently and significantly (p < 0.05) improved post-ischemic recovery of cardiac output, external heart power, LV developing pressure and dp/dt_max, compared with the vehicle (0.01% dimethyl sulfoxide). Ac-DEVD-CHO was similarly effective when given before reperfusion. Ac-DEVD-CHO blocked ischemia/reperfusion-induced caspase-3 activation, but cardiomyocyte apoptosis was unaffected. Troponin I cleavage was not inhibited by Ac-DEVD-CHO.

CONCLUSIONS: Caspase-3 is activated in stunned myocardium. Inhibition of caspase-3 by Ac-DEVD-CHO significantly improves post-ischemic contractile recovery of stunned myocardium, even when given after the onset of ischemia. The mechanism(s) of protection by Ac-DEVD-CHO appear to be independent of apoptosis. Inhibition of caspase-3 is a novel therapeutic strategy to improve functional recovery of stunned myocardium.

Abbreviations and Acronyms   DMSO   dimethyl sulfoxide   DNA   deoxyribonucleic acid   LV   left ventricular   LVP   left ventricular pressure   MI   myocardial infarction

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