Caspase inhibition prevents cardiac dysfunction and heart apoptosis in a rat model of sepsis.
Despite intensive therapy, severe septic shock is commonly associated with myocardial dysfunction and death in humans. No new therapies have proven efficiency against cardiovascular alterations in sepsis. Here, we addressed the question of a beneficial effect of pharmacological inhibition of caspases on myocardial dysfunction following endotoxin treatment. Hearts from rats treated with endotoxin (10 mg/kg, intravenously) were isolated 4 h posttreatment for analysis. Assessment of myocardial contractility ex vivo and detection of apoptosis were performed. Hearts from endotoxin-treated rats displayed multiple caspase activities and also typical apoptosis pattern as detected by TUNEL, DNA fragmentation assays, and cytochrome c release as compared with control rats. z-VAD.fmk (3 mg/kg, intravenously), a broad spectrum caspase inhibitor (but not the irrelevant peptide z-FA.fmk), in coinjection with endotoxin, not only reduced caspase activities and nuclear apoptosis but also completely prevented endotoxin-induced myocardial dysfunction evaluated 4 h and even 14 h after endotoxin challenge. These data indicate that caspase activation plays an important role in myocardial cell dysfunction. Moreover, these results suggest that inhibitors of caspases may have important therapeutic applications in sepsis.
Nevière
R
R
INSERM U459, Faculté de Médecine, EA 2689, Pavillon Vancostenobel, Faculté de Médecine, and Département de Physiologie, Faculté de Médecine, Lille Cedex, France.
Fauvel
H
H
Chopin
C
C
Formstecher
P
P
Marchetti
P
P
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D061945:Caspase Inhibitors; D004731:Endotoxins; D006321:Heart / Q000503:physiopathology*; D008297:Male; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000473:pathology*
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D004731:Endotoxins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone