Document Detail


Differential effects of caspase inhibitors on endotoxin-induced myocardial dysfunction and heart apoptosis.
MedLine Citation:
PMID:  11247771     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
H Fauvel; P Marchetti; C Chopin; P Formstecher; R Nevière
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  280     ISSN:  0363-6135     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2001 Apr 
Date Detail:
Created Date:  2001-03-15     Completed Date:  2001-04-19     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1608-14     Citation Subset:  IM    
Affiliation:
Institut National de la Santé et de la Recherche Médicale U459, Lille Cedex, 59045, France.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Chloromethyl Ketones / pharmacology
Animals
Apoptosis / drug effects*
Blood Pressure
Caspases / antagonists & inhibitors*
Coronary Circulation / drug effects,  physiology
Cysteine Proteinase Inhibitors / pharmacology*
DNA Fragmentation
Endotoxins / toxicity*
Heart / drug effects,  physiology*,  physiopathology
Hemodynamics / drug effects*,  physiology
Male
Myocardial Contraction / drug effects
Myocardium / cytology*,  pathology
Oligopeptides / pharmacology
Rats
Rats, Sprague-Dawley
Time Factors
Ventricular Function, Left / drug effects,  physiology
Chemical
Reg. No./Substance:
0/Amino Acid Chloromethyl Ketones; 0/Cysteine Proteinase Inhibitors; 0/Endotoxins; 0/N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; 0/Oligopeptides; 0/benzyloxycarbonyl aspartyl-glutamyl-valyl-aspartyl-chloromethyl ketone; 0/benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; EC 3.4.22.-/Caspases

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