| Differential effects of caspase inhibitors on endotoxin-induced myocardial dysfunction and heart apoptosis. | |
MedLine Citation:
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PMID: 11247771 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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:
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H Fauvel; P Marchetti; C Chopin; P Formstecher; R Nevière |
Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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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:
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Created Date: 2001-03-15 Completed Date: 2001-04-19 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 100901228 Medline TA: Am J Physiol Heart Circ Physiol Country: United States |
Other Details:
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Languages: eng Pagination: H1608-14 Citation Subset: IM |
Affiliation:
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Institut National de la Santé et de la Recherche Médicale U459, Lille Cedex, 59045, France. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Chloromethyl Ketones
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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:
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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 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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