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

被引:90
作者
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.
机构
[1] Thomas Jefferson Univ, Dept Emergency Med, Philadelphia, PA 19107 USA
[2] Thomas Jefferson Univ, Ctr Translat Med, Philadelphia, PA 19107 USA
[3] Thomas Jefferson Univ, Div Nephrol, Philadelphia, PA 19107 USA
[4] Inotek Pharmaceut Corp, Cummings Ctr, Beverly, MA USA
关键词
apoptosis; thioredoxin; ischemia; nitric oxide; reperfusion;
D O I
10.1161/CIRCULATIONAHA.106.625061
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-PyP5+ (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-PyP5+ 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.
引用
收藏
页码:1395 / 1402
页数:8
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