Published Online
on September 11, 2006

A more recent version of this article appeared on September 26, 2006

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Submitted on March 7, 2006
Revised on July 14, 2006
Accepted on July 21, 2006

Nitrative Inactivation of Thioredoxin-1 and Its Role in Postischemic Myocardial Apoptosis

Ling Tao MD, PhD, Xiangying Jiao MD, PhD, Erhe Gao MD, PhD, Wayne B. Lau MD, Yuexing Yuan PhD, Bernard Lopez MD, Theodore Christopher MD, Satish P. RamachandraRao PhD, William Williams PhD, Garry Southan PhD, Kumar Sharma MD, Walter Koch PhD, and Xin L. Ma MD, PhD^*

From the Department of Emergency Medicine (L.T., X.J., W.B.L., Y.Y., B.L., T.C., X.L.M.), Center for Translational Medicine (E.G., W.K.), and Division of Nephrology (S.P.R., K.S.), Thomas Jefferson University, Philadelphia, Pa, and Inotek Pharmaceuticals Corporation (W.W., G.S.), Cummings Center, Beverly, Mass.

^* To whom correspondence should be addressed. E-mail: Xin.Ma{at}Jefferson.edu.

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.

Key words: apoptosis • thioredoxin • ischemia • nitric oxide • reperfusion

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