Mechanisms of the protective action of diethyldithiocarbamate-iron complex on acute cardiac allograft rejection.
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.
Pieper
Galen M
GM
Division of Transplant Surgery, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, USA. gmpieper@mcw.edu
Nilakantan
Vani
V
Hilton
Gail
G
Halligan
Nadine L N
NL
Felix
Christopher C
CC
Kampalath
Bal
B
Khanna
Ashwani K
AK
Roza
Allan M
AM
Johnson
Christopher P
CP
Adams
Mark B
MB
D000208:Acute Disease; D000818:Animals; D004050:Ditiocarb / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D005296:Ferrous Compounds / Q000494:pharmacology*; D015870:Gene Expression; D006084:Graft Rejection / Q000188:drug therapy* / Q000378:metabolism; D016027:Heart Transplantation; D007371:Interferon-gamma / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D014184:Transplantation, Homologous
D005296:Ferrous Compounds; D016328:NF-kappa B; C085124:diethyldithiocarbamate iron(II); D009569:Nitric Oxide; D007371:Interferon-gamma; D004050:Ditiocarb; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat