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Conversion of Death Signal into Survival Signal by Redox Signaling

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Abstract

Reperfusion of ischemic myocardium produces reactive oxygen species (ROS) and results in apoptotic cell death and DNA fragmentation. Several redox-sensitive anti- and pro-apoptotic transcription factors including nuclear factor κB (NF-κB) and heterodimeric transcription factor AP-1 progressively and steadily increase in the heart as a function of the duration of ischemia and reperfusion. When the heart is adapted to ischemic stress by repeated short-term ischemia and reperfusion, NF-κB remains high, while AP-1 is lowered to almost baseline value. The anti-apoptotic geneBcl-2 is downregulated in the ischemic/reperfused heart, while it is upregulated in the adapted myocardium. Cardioprotective abilities of the adapted myocardium are abolished when heart is pre-perfused with N-acetyl cysteine to scavenge ROS, suggesting a role of redox signaling. Mammalian heart is protected by several defense systems, which include, among others, the redox-regulated protein thioredoxin. Reperfusion of ischemic myocardium results in the downregulation of thioredoxin 1 (Trx 1) expression, which was upregulated in the adapted myocardium. The increased expression of Trx 1 is completely blocked with an inhibitor of Trx 1, cis-diammine-dichloroplatinum, which also abolished cardioprotection afforded by ischemic adaptation. The cardioprotective role of Trx 1 is further confirmed with transgenic mouse hearts overexpressing Trx 1. The Trx 1 mouse hearts displayed significantly improved post-ischemic ventricular recovery and reduced myocardial infarct size and apoptosis compared to the corresponding wild-type mouse hearts. The results of this study implicate a crucial role of redox signaling in transmitting anti-death signal.

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  1. Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT, 06030-1110, USA

    D. K. Das & N. Maulik

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Das, D.K., Maulik, N. Conversion of Death Signal into Survival Signal by Redox Signaling. Biochemistry (Moscow) 69, 10–17 (2004). https://doi.org/10.1023/B:BIRY.0000016345.19027.54

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