Caspase inhibition and limitation of myocardial infarct size: protection against lethal reperfusion injury.
Ischaemia-reperfusion injury causes cell death by both necrosis and apoptosis. Caspase activation is a major event in apoptosis. We therefore examined the effect of caspase inhibitors during reperfusion upon myocardial infarction. Rat isolated hearts were subjected to 35 min coronary occlusion and 120 min reperfusion. Treatment groups were perfused with caspase inhibitors during early reperfusion. We assessed a non-selective caspase inhibitor (Z-VAD. fmk, 0.1 microM), a caspase-8 inhibitor (Z-IETD.fmk, 0.07 microM), a caspase-9 inhibitor (Z-LEHD.fmk, 0.07 microM) and a caspase-3 inhibitor (Ac-DEVD.cmk, 0.07 microM). All caspase inhibitors limited infarct size (infarct-risk ratio per cent: control 38.5+/-2.6; Z-VAD. fmk 24.6+/-3.4; Z-LEHD.fmk 19.3+/-2.4; Z-IETD.fmk 23.0+/-5.4; Ac-DEVD.cmk 27.8+/-3.3; P<0.05 when compared with control value, 1-way ANOVA). We conclude that caspase inhibition during early reperfusion protects myocardium against lethal reperfusion injury.
Mocanu
M M
MM
The Hatter Institute, Division of Cardiology, University College Hospitals & Medical School, Grafton Way, London, WC1E 6DE.
Baxter
G F
GF
Yellon
D M
DM
D000590:Amino Acid Chloromethyl Ketones / Q000627:therapeutic use; D000818:Animals; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control*; D009842:Oligopeptides / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; C403754:benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone