Document Detail

U937 cell necrosis mediated by peroxynitrite is not caused by depletion of ATP and is prevented by arachidonate via an ATP-dependent mechanism.
MedLine Citation:
PMID:  15689569     Owner:  NLM     Status:  MEDLINE    
Exposure of U937 cells to an otherwise nontoxic concentration of peroxynitrite promotes a rapid necrotic response in the presence of pharmacological inhibitors of phospholipase A2. A 12-fold higher concentration of the oxidant, in the absence of additional treatments, caused remarkably greater DNA single-strand breakage, delayed formation of H2O2, and depletion of reduced glutathione but an identical level of toxicity. Cell death was prevented in both circumstances by nanomolar levels of arachidonic acid or by cyclosporin A via mechanisms unrelated to elimination of the above effects and was causally linked to prevention of mitochondrial permeability transition. Treatment with a high dose of peroxynitrite for 30 min caused an approximately 40% decline in ATP, both in the absence and presence of arachidonate, whereas only a small, arachidonic acid-sensitive reduction of the ATP pool was detected in cells treated with the low dose of peroxynitrite and the phospholipase A2 inhibitor. ATP-predepleted cells, however, were hypersensitive to peroxynitrite, and under these conditions, toxicity was not prevented by arachidonate. The above findings were reproduced in another promonocytic cell line, THP-1 cells. We concluded that the rapid necrotic response triggered by peroxynitrite in monocytes is mediated by a regulated process, not by ATP depletion, associated with reduced arachidonate availability. Supplementation of exogenous arachidonic acid always rescued cells via an ATP-dependent survival pathway.
Orazio Cantoni; Andrea Guidarelli; Letizia Palomba; Mara Fiorani
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-02-02
Journal Detail:
Title:  Molecular pharmacology     Volume:  67     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2005 May 
Date Detail:
Created Date:  2005-04-18     Completed Date:  2005-06-15     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1399-405     Citation Subset:  IM    
Istituto di Farmacologia e Farmacognosia, Università Degli Studi di Urbino Carlo Bo, Urbino (PU), Italy.
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MeSH Terms
Adenosine Triphosphate / metabolism*
Apoptosis / drug effects,  physiology
Arachidonic Acid / metabolism*
Dose-Response Relationship, Drug
Monocytes / drug effects*,  metabolism*
Necrosis / metabolism,  prevention & control
Peroxynitrous Acid / toxicity*
U937 Cells
Reg. No./Substance:
14691-52-2/Peroxynitrous Acid; 506-32-1/Arachidonic Acid; 56-65-5/Adenosine Triphosphate

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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