Mechanisms of the protective action of diethyldithiocarbamate-iron complex on acute cardiac allograft rejection

Abstract

In this study, we examined the actions of diethyldithiocarbamate-iron (DETC-Fe) complex in acute graft rejection heterotopically transplanted rat hearts. Chronic treatment with DETC-Fe inhibited the increase in plasma nitric oxide (NO) metabolites and nitrosylation of myocardial heme protein as determined by electron paramagnetic resonance (EPR) spectroscopy. Pulse injection with DETC-Fe normalized NO metabolites. We verified intragraft trapping of NO in vivo by pulse injection with DETC-Fe by the detection within allografts of an anisotropic triplet EPR signal for DETC-Fe-NO adduct with resonance positions ( g tensor factors for perpendicular and parallel components, respectively g ⊥ = 2.038 and g ∥ = 2.02; hyperfine coupling of 12.5 G). DETC-Fe prolonged graft survival and decreased histological rejection scores. DNA binding activity for nuclear factor (NF)-κB and activator protein-1 was increased in allografts and prevented by DETC-Fe. Abrogation of the activation of NF-κB by DETC-Fe was associated with increased IκBα inhibitory protein. Western blotting and RT-PCR analysis revealed that DETC-Fe inhibited inducible NO synthase protein and gene expression. Gene expression for the proinflammatory cytokine interferon-γ was also decreased by DETC-Fe. Thus DETC-Fe limits NF-κB-dependent gene expression and possesses significant immunosuppressive properties.