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Mechanisms of the protective action of diethyldithiocarbamate-iron complex on acute cardiac allograft rejection. Am J Physiol Heart Circ Physiol 2003 May;284(5):H1542-51

Date

04/08/2003

Pubmed ID

12679325

DOI

10.1152/ajpheart.00913.2002

Scopus ID

2-s2.0-0037405775   13 Citations

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( perpendicular ) = 2.038 and g( parallel ) = 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)-kappaB and activator protein-1 was increased in allografts and prevented by DETC-Fe. Abrogation of the activation of NF-kappaB by DETC-Fe was associated with increased IkappaBalpha 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-kappaB-dependent gene expression and possesses significant immunosuppressive properties.

Author List

Pieper GM, Nilakantan V, Hilton G, Halligan NL, Felix CC, Kampalath B, Khanna AK, Roza AM, Johnson CP, Adams MB

Authors

Christopher P. Johnson MD Professor in the Surgery department at Medical College of Wisconsin
Allan M. Roza MD Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Acute Disease
Animals
Ditiocarb
Electron Spin Resonance Spectroscopy
Ferrous Compounds
Gene Expression
Graft Rejection
Heart Transplantation
Interferon-gamma
NF-kappa B
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type II
Rats
Rats, Inbred Lew
Rats, Inbred WF
Transplantation, Homologous
jenkins-FCD Prod-478 d1509cf07a111124a2d122fd3df854cc0b993c00