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Am J Physiol Heart Circ Physiol 284: H1542-H1551, 2003; doi:10.1152/ajpheart.00913.2002
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Vol. 284, Issue 5, H1542-H1551, May 2003

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

Galen M. Pieper1,2,3, Vani Nilakantan1, Gail Hilton1, Nadine L. N. Halligan1, Christopher C. Felix4, Bal Kampalath5, Ashwani K. Khanna3,6, Allan M. Roza1, Christopher P. Johnson1, and Mark B. Adams1

1 Division of Transplant Surgery, 2 Free Radical Research Center, 3 Cardiovascular Research Center, 4 Biophysics Research Institute, 5 Department of Pathology, and 6 Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

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 gperp  = 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)-kappa B and activator protein-1 was increased in allografts and prevented by DETC-Fe. Abrogation of the activation of NF-kappa B by DETC-Fe was associated with increased Ikappa Balpha 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-gamma was also decreased by DETC-Fe. Thus DETC-Fe limits NF-kappa B-dependent gene expression and possesses significant immunosuppressive properties.

nitric oxide synthase; interferon-gamma ; electron paramagnetic resonance spectroscopy; nuclear factor-kappa B; activator protein-1


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