Nitrative inactivation of thioredoxin-1 and its role in postischemic myocardial apoptosis
| Autor: | William Williams, Walter J. Koch, Xiangying Jiao, Bernard L. Lopez, Kumar Sharma, Garry Southan, Erhe Gao, Wayne Bond Lau, Theodore A. Christopher, Yuexing Yuan, Ling Tao, Xin L. Ma, Satish P. RamachandraRao |
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| Rok vydání: | 2006 |
| Předmět: |
Male
animal structures Antioxidant Cardiotonic Agents MAP Kinase Signaling System Metalloporphyrins medicine.medical_treatment Ischemia Myocardial Ischemia Apoptosis Myocardial Reperfusion Injury Pharmacology medicine.disease_cause MAP Kinase Kinase Kinase 5 p38 Mitogen-Activated Protein Kinases Nitric oxide Superoxide dismutase Cyclic N-Oxides chemistry.chemical_compound Mice Thioredoxins In vivo Physiology (medical) Peroxynitrous Acid medicine Animals Humans biology business.industry Myocardium Imidazoles Free Radical Scavengers medicine.disease Oxidative Stress chemistry Biochemistry Amino Acid Substitution Molsidomine biology.protein Mutagenesis Site-Directed Thioredoxin Cardiology and Cardiovascular Medicine business Oxidation-Reduction Oxidative stress NADP |
| Zdroj: | Circulation. 114(13) |
| ISSN: | 1524-4539 |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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