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Inhibition of nitrosylation, nitration, lymphocyte proliferation, and gene expression in acute and delayed cardiac allograft rejection by an orally active dithiocarbamate. J Cardiovasc Pharmacol 2004 Apr;43(4):522-30

Date

04/16/2004

Pubmed ID

15085063

DOI

10.1097/00005344-200404000-00007

Scopus ID

2-s2.0-3042575644   9 Citations

Abstract

Dithiocarbamate derivatives sequester metals such as iron and may have benefits in inflammatory diseases. We examined the actions of a new dithiocarbamate-based oral formulation, NOX-700, on protein modification by nitric oxide (NO), gene expression, and lymphocyte proliferation in a model of acute and delayed cardiac rejection. Chronic treatment with NOX-700 prolonged graft survival. In combination with low-dose cyclosporine (CsA), NOX-700 produced a synergistic action to prolong graft survival. NOX-700 decreased myocardial heme nitrosylation. A single bolus injection with NOX-700 in untreated recipients did not decrease heme nitrosylation but normalized NO metabolites and caused the formation of a mononitrosyl iron complex indicating NO scavenging in vivo. NOX-700 alone given with CsA inhibited protein nitration. NOX-700 or CsA each alone decreased intragraft inflammatory cell infiltration. NOX-700 also potentiated the CsA-induced inhibition of splenocyte proliferation ex vivo stimulated by concanavalin A. In splenocytes derived from treated rats but stimulated ex vivo in a mixed lymphocyte response (MLR), interferon-gamma and cyclin D3 gene expression was inhibited by NOX-700 suggesting down-regulation of lymphocyte activation and proliferation by in vivo treatment. These studies suggest that NOX-700 is protective in cardiac rejection, in part, by scavenging of NO and by limiting lymphocyte activation infiltration.

Author List

Pieper GM, Khanna AK, Kampalath BN, Felix CC, Hilton G, Johnson CP, Adams MB, Roza AM

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

Administration, Oral
Animals
Cell Division
Gene Expression Regulation
Graft Rejection
Heart Transplantation
Lymphocytes
Nitrates
Nitric Oxide
Nitrites
Rats
Rats, Inbred Lew
Rats, Wistar
Thiocarbamates
Transplantation, Homologous
jenkins-FCD Prod-478 d1509cf07a111124a2d122fd3df854cc0b993c00