| Nitrative inactivation of thioredoxin-1 and its role in postischemic myocardial apoptosis. | |
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MedLine Citation:
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PMID: 16966583 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Intracellular proteins involved in oxidative stress and apoptosis are nitrated in diseased tissues but not in normal tissues; definitive evidence to support a causative link between a specific protein that is nitratively modified with tissue injury in a specific disease is limited, however. The aims of the present study were to determine whether thioredoxin (Trx), a novel antioxidant and antiapoptotic molecule, is susceptible to nitrative inactivation and to establish a causative link between Trx nitration and postischemic myocardial apoptosis. METHODS AND RESULTS: In vitro exposure of human Trx-1 to 3-morpholinosydnonimine resulted in significant Trx-1 nitration and almost abolished Trx-1 activity. 3-morpholinosydnonimine-induced nitrative Trx-1 inactivation was completely blocked by MnTE-2-PyP(5+) (a superoxide dismutase mimetic) and markedly attenuated by PTIO (a nitric oxide scavenger). Administration of either reduced or oxidized Trx-1 in vivo attenuated myocardial ischemia/reperfusion injury (>50% reduction in apoptosis and infarct size, P<0.01). However, administration of nitrated Trx-1 failed to exert a cardioprotective effect. In cardiac tissues obtained from ischemic/reperfused heart, significant Trx-1 nitration was detected, Trx activity was markedly inhibited, Trx-1/ASK1 (apoptosis signal-regulating kinase-1) complex formation was abolished, and apoptosis signal-regulating kinase-1 activity was increased. Treatment with either FP15 (a peroxynitrite decomposition catalyst) or MnTE-2-PyP(5+) 10 minutes before reperfusion blocked nitrative Trx inactivation, attenuated apoptosis signal-regulating kinase-1 activation, and reduced postischemic myocardial apoptosis. CONCLUSIONS: These results strongly suggest that nitrative inactivation of Trx plays a proapoptotic role under those pathological conditions in which production of reactive nitrogen species is increased and that antinitrating treatment may have therapeutic value in those diseases, such as myocardial ischemia/reperfusion, in which pathological apoptosis is increased. |
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Authors:
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Ling Tao; Xiangying Jiao; Erhe Gao; Wayne B Lau; Yuexing Yuan; Bernard Lopez; Theodore Christopher; Satish P RamachandraRao; William Williams; Garry Southan; Kumar Sharma; Walter Koch; Xin L Ma |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2006-09-11 |
Journal Detail:
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Title: Circulation Volume: 114 ISSN: 1524-4539 ISO Abbreviation: Circulation Publication Date: 2006 Sep |
Date Detail:
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Created Date: 2006-09-26 Completed Date: 2006-10-26 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0147763 Medline TA: Circulation Country: United States |
Other Details:
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Languages: eng Pagination: 1395-402 Citation Subset: AIM; IM |
Affiliation:
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Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Substitution Animals Apoptosis / physiology* Cardiotonic Agents / antagonists & inhibitors, pharmacology, therapeutic use Cyclic N-Oxides / pharmacology Free Radical Scavengers / pharmacology Humans Imidazoles / pharmacology MAP Kinase Kinase Kinase 5 / metabolism MAP Kinase Signaling System / drug effects Male Metalloporphyrins / pharmacology, therapeutic use Mice Molsidomine / analogs & derivatives*, antagonists & inhibitors, pharmacology Mutagenesis, Site-Directed Myocardial Ischemia / metabolism*, pathology Myocardial Reperfusion Injury / drug therapy Myocardium / pathology* NADP / metabolism Oxidation-Reduction Oxidative Stress Peroxynitrous Acid / pharmacology Thioredoxins / antagonists & inhibitors*, therapeutic use p38 Mitogen-Activated Protein Kinases / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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2R01HL-63828/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cardiotonic Agents; 0/Cyclic N-Oxides; 0/FeCl tetrakis-2-(triethyleneglycolmonomethylether)pyridylporphyrin; 0/Free Radical Scavengers; 0/Imidazoles; 0/Metalloporphyrins; 0/TXN protein, human; 0/manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin; 14691-52-2/Peroxynitrous Acid; 18390-00-6/2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; 25717-80-0/Molsidomine; 33876-97-0/3-morpholino-sydnonimine; 52500-60-4/Thioredoxins; 53-59-8/NADP; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 2.7.11.25/MAP Kinase Kinase Kinase 5 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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