Nitrative inactivation of thioredoxin-1 and its role in postischemic myocardial apoptosis

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

Research output: Contribution to journalArticle

74 Citations (Scopus)

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. 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 (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 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.

Original languageEnglish (US)
Pages (from-to)1395-1402
Number of pages8
JournalCirculation
Volume114
Issue number13
DOIs
StatePublished - Sep 1 2006
Externally publishedYes

Fingerprint

Thioredoxins
Apoptosis
MAP Kinase Kinase Kinase 5
Myocardial Ischemia
Myocardial Reperfusion Injury
Reactive Nitrogen Species
Myocardial Reperfusion
Peroxynitrous Acid
Reperfusion Injury
Superoxide Dismutase
Reperfusion
Nitric Oxide
Proteins
Oxidative Stress

Keywords

  • Apoptosis
  • Ischemia
  • Nitric oxide
  • Reperfusion
  • Thioredoxin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Tao, L., Jiao, X., Gao, E., Lau, W. B., Yuan, Y., Lopez, B., ... Ma, X. L. (2006). Nitrative inactivation of thioredoxin-1 and its role in postischemic myocardial apoptosis. Circulation, 114(13), 1395-1402. https://doi.org/10.1161/CIRCULATIONAHA.106.625061

Nitrative inactivation of thioredoxin-1 and its role in postischemic myocardial apoptosis. / Tao, Ling; Jiao, Xiangying; Gao, Erhe; Lau, Wayne B.; Yuan, Yuexing; Lopez, Bernard; Christopher, Theodore; Ramachandrarao, Satish P.; Williams, William; Southan, Garry; Sharma, Kumar; Koch, Walter; Ma, Xin L.

In: Circulation, Vol. 114, No. 13, 01.09.2006, p. 1395-1402.

Research output: Contribution to journalArticle

Tao, L, Jiao, X, Gao, E, Lau, WB, Yuan, Y, Lopez, B, Christopher, T, Ramachandrarao, SP, Williams, W, Southan, G, Sharma, K, Koch, W & Ma, XL 2006, 'Nitrative inactivation of thioredoxin-1 and its role in postischemic myocardial apoptosis', Circulation, vol. 114, no. 13, pp. 1395-1402. https://doi.org/10.1161/CIRCULATIONAHA.106.625061
Tao, Ling ; Jiao, Xiangying ; Gao, Erhe ; Lau, Wayne B. ; Yuan, Yuexing ; Lopez, Bernard ; Christopher, Theodore ; Ramachandrarao, Satish P. ; Williams, William ; Southan, Garry ; Sharma, Kumar ; Koch, Walter ; Ma, Xin L. / Nitrative inactivation of thioredoxin-1 and its role in postischemic myocardial apoptosis. In: Circulation. 2006 ; Vol. 114, No. 13. pp. 1395-1402.
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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. 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 (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 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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AU - Tao, Ling

AU - Jiao, Xiangying

AU - Gao, Erhe

AU - Lau, Wayne B.

AU - Yuan, Yuexing

AU - Lopez, Bernard

AU - Christopher, Theodore

AU - Ramachandrarao, Satish P.

AU - Williams, William

AU - Southan, Garry

AU - Sharma, Kumar

AU - Koch, Walter

AU - Ma, Xin L.

PY - 2006/9/1

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N2 - 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 (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 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.

AB - 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 (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 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.

KW - Apoptosis

KW - Ischemia

KW - Nitric oxide

KW - Reperfusion

KW - Thioredoxin

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