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Am J Physiol Heart Circ Physiol 280: H1608-H1614, 2001;
0363-6135/01 $5.00
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Vol. 280, Issue 4, H1608-H1614, April 2001

Differential effects of caspase inhibitors on endotoxin-induced myocardial dysfunction and heart apoptosis

Harold Fauvel1,*, Philippe Marchetti1,*, Claude Chopin3, Pierre Formstecher1, and Rémi Nevière2,3

1 Institut National de la Santé et de la Recherche Médicale U459 and 2 Département de Physiologie, Faculté de Médecine, Lille Cedex, 59045, and 3 EA 2689, Faculté de Médecine, Lille Cedex, 59037, France

Endotoxin is one of the major factors causing myocardial depression and death during sepsis in humans. Recently, it was reported that endotoxin may induce cardiomyocyte apoptosis. Also, multiple caspase activation has been implicated in endotoxin-induced apoptosis in several organ systems. In this study, we investigated whether endotoxin would increase myocardial caspase activities and evaluated the effects of in vivo administration (3 mg/kg) of the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone(z-VAD.fmk), the caspase-3-like inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp-chloromethylketone (z-DEVD.cmk), and the caspase-1-like inhibitor acetyl-Tyr-Val-Ala-Asp-chloromethylketone (Ac-YVAD. fmk), on endotoxin-induced myocardial dysfunction and apoptosis. Endotoxin administration (10 mg/kg iv) induced myocardial contractile dysfunction that was associated with caspase activity increases and nuclear apoptosis. Broad-spectrum z-VAD.fmk and z-DEVD.cmk improved endotoxin-induced myocardial dysfunction and reduced caspase activation and nuclear apoptosis when given immediately and 2 h after endotoxin. In contrast, no effects of Ac-YVAD.fmk were observed on myocardial function and caspase-induced apoptosis. Administration of caspase inhibitors 4 h after endotoxin treatment was not able to protect the rat heart from myocardial dysfunction and nuclear apoptosis. These observations provide evidence that in our model, caspase activation plays a role in endotoxin-induced myocardial apoptosis. Caspase inhibition strategy may represent a therapeutic approach to endotoxin-induced myocardial dysfunction.

lipopolysaccharide; cell death; proteases

* H. Fauvel and P. Marchetti contributed equally to this work.




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