| Poly(ADP-ribose) polymerase inhibition in oxidant-stressed endothelial cells prevents oncosis and permits caspase activation and apoptosis. | |
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MedLine Citation:
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PMID: 10471325 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Endothelial cells (EC) are subject to oxidative-induced cell death. Activation of poly(ADP-ribose) polymerase (PARP) occurs early in oxidant-induced EC injury and putatively mediates cell death by depleting its substrate, NAD(+). In this study, the role of PARP in H(2)O(2)-induced EC death was investigated. EC were exposed to oxidant stress and viability continuously monitored using fluorescent dye exclusion. Inhibition of PARP with 1, 5-dihydroxyisoquinoline (DIQ) delayed the time course of oxidant-induced EC death. Concurrent addition of the protein synthesis inhibitor, cycloheximide, or the endonuclease inhibitor, aurintricarboxylic acid, to PARP-inhibited cells further delayed the onset and attenuated the extent of H(2)O(2)-induced cell lysis, consistent with an active mode of cell death. Caspase-3-like activity, a hallmark of apoptosis, was negligible in oxidant-treated EC alone, however, inhibition of PARP by 3-aminobenzamide or DIQ dramatically increased caspase-3-like activity. Morphological assessment confirmed that the primary mode of death in oxidant-stressed EC was oncosis. However, following PARP inhibition, the cells switched to apoptosis. Since inflammation is associated with oncosis and not apoptosis, the results presented here could explain the beneficial effects seen with PARP inhibition in various in vivo models of oxidant injury and provide a mechanism to manipulate this injury into a state of cell death that could ultimately be controlled. |
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Authors:
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J A Walisser; R L Thies |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Experimental cell research Volume: 251 ISSN: 0014-4827 ISO Abbreviation: Exp. Cell Res. Publication Date: 1999 Sep |
Date Detail:
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Created Date: 1999-10-05 Completed Date: 1999-10-05 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0373226 Medline TA: Exp Cell Res Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 401-13 Citation Subset: IM |
Copyright Information:
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Copyright 1999 Academic Press. |
Affiliation:
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Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, British Columbia, V6T 1Z3, Canada. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / physiology* Aurintricarboxylic Acid / pharmacology Benzamides / pharmacology Caspase 3 Caspases / metabolism Cattle Cell Death / physiology* Cell Membrane / metabolism Cells, Cultured Cycloheximide / pharmacology Endothelium, Vascular / cytology, physiology* Energy Metabolism Enzyme Activation Hydrogen Peroxide / pharmacology Inflammation / metabolism Isoquinolines / pharmacology Oxidants / pharmacology Oxidative Stress / physiology* Poly(ADP-ribose) Polymerases / antagonists & inhibitors* |
| Chemical | |
Reg. No./Substance:
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0/Benzamides; 0/Isoquinolines; 0/Oxidants; 3544-24-9/3-aminobenzamide; 4431-00-9/Aurintricarboxylic Acid; 5154-02-9/1,5-dihydroxyisoquinoline; 66-81-9/Cycloheximide; 7722-84-1/Hydrogen Peroxide; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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