H. Ruetten et al., Inhibition of caspase-3 improves contractile recovery of stunned myocardium, independent of apoptosis-inhibitory effects, J AM COL C, 38(7), 2001, pp. 2063-2070
Citations number
23
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
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.