Myocardial ischemia and reperfusion lead to myocyte cell death, at least in part, by an apoptotic mechanism.
Caspases are a conserved family of
proteases that play an essential role in the execution of apoptosis; however, their potential contribution to ischemic myocardial cell death is largely unknown. To examine their role in this process, we subjected rabbits to 30 min of coronary artery occlusion followed by 3 h of reperfusion. Immunoblot analyses revealed that caspases-2, -3 and -7 were proteolytically activated during
myocardial ischemia and reperfusion in vivo. In addition, the well-characterized
caspase substrate
poly(ADP-ribose) polymerase (PARP) was selectively cleaved into its signature apoptotic fragment in ischemic/reperfused myocardium. Systemic administration of the broad-spectrum
caspase inhibitor acetyl-Tyr-Val-
Ala-Asp chloromethylketone (
YVAD-cmk, 4.8 mg/kg) partially blocked
caspase activation and dramatically reduced the percentage of terminal dUTP deoyxynucleotidyl-
transferase nick end-labeling (TUNEL)-positive myocyte nuclei in the
infarct region (3.9+/-0.8%v 13.0+/-2.2% in control animals, P=0.012). Moreover,
YVAD-cmk reduced
myocardial infarct size by approximately 31% (31.1+/-3.3%v 45.3+/-4.9% in control animals, P=0.032). These results indicate that
caspases are critical mediators of myocardial injury induced by
ischemia and reperfusion in vivo, and they suggest that
caspase inhibition may be therapeutically beneficial in
myocardial infarction.