title: Nitrative inactivation of thioredoxin-1 and its role in postischemic myocardial apoptosis.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Tao
authors.forename: Xiangying
authors.initials: X
authors.lastname: Jiao
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Wayne B
authors.initials: WB
authors.lastname: Lau
authors.forename: Yuexing
authors.initials: Y
authors.lastname: Yuan
authors.forename: Bernard
authors.initials: B
authors.lastname: Lopez
authors.forename: Theodore
authors.initials: T
authors.lastname: Christopher
authors.forename: Satish P
authors.initials: SP
authors.lastname: RamachandraRao
authors.forename: William
authors.initials: W
authors.lastname: Williams
authors.forename: Garry
authors.initials: G
authors.lastname: Southan
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
authors.forename: Walter
authors.initials: W
authors.lastname: Koch
authors.forename: Xin L
authors.initials: XL
authors.lastname: Ma
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D003497:Cyclic N-Oxides / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D009206:Myocardium / Q000473:pathology*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000494:pharmacology; D013879:Thioredoxins / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D003497:Cyclic N-Oxides; C471469:FeCl tetrakis-2-(triethyleneglycolmonomethylether)pyridylporphyrin; D016166:Free Radical Scavengers; D007093:Imidazoles; D008665:Metalloporphyrins; C491203:TXN protein, human; C431023:manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin; D030421:Peroxynitrous Acid; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D013879:Thioredoxins; D009249:NADP; C002385:linsidomine; D008981:Molsidomine; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5