Antioxidant Treatment Inhibits Activation of Myocardial Nuclear Factor κB and Inhibits Nitrosylation of Myocardial Heme Protein in Cardiac Transplant Rejection

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Abstract
Nitric oxide production via inducible nitric oxide synthase (iNOS) is believed to play a role in cardiac allograft rejection. Previously, we showed that antioxidants can significantly prolong cardiac graft survival, but the nature of this protection is unknown. In the present study, we examined the protective effect of another antioxidant, dimethylthiourea (DMTU), in a model of cardiac allograft rejection. Specifically, we hypothesized that DMTU would prolong graft survival and decrease activation of nuclear factor-κB (NF-κB), an important redox-sensitive transcription factor necessary for iNOS gene expression. NF-κB was activated by twofold as early as postoperative day 2 in allografts. NF-κB activation in allografts progressed to a peak of ninefold by postoperative day and remained increased until postoperative day 6. No activation of NF-κB was observed in isografts for comparable time periods. Treatment with DMTU resulted in a significant prolongation of graft survival. This beneficial effect was associated with diminished activation of myocardial NF-κB. Treatment with DMTU also resulted in decreased formation of iron-nitrosylprotein complexes as evidenced by electron paramagnetic resonance spectroscopy. These studies provide evidence that reactive oxygen plays a significant role in signal transduction for activation via the transcription factor, NF-κB, thereby modulating distal actions and consequences of iNOS-derived nitric oxide.