title: Inhibition of nitrosylation, nitration, lymphocyte proliferation, and gene expression in acute and delayed cardiac allograft rejection by an orally active dithiocarbamate.
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.
authors.affiliation: Department of Surgery (Division of Transplant Surgery), Medical College of Wisconsin, Milwaukee, WI 53226, USA. gmpieper@mcw.edu
authors.forename: Galen M
authors.initials: GM
authors.lastname: Pieper
authors.forename: Ashwani K
authors.initials: AK
authors.lastname: Khanna
authors.forename: Bal N
authors.initials: BN
authors.lastname: Kampalath
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Felix
authors.forename: Gail
authors.initials: G
authors.lastname: Hilton
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Johnson
authors.forename: Mark B
authors.initials: MB
authors.lastname: Adams
authors.forename: Allan M
authors.initials: AM
authors.lastname: Roza
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006084:Graft Rejection / Q000188:drug therapy* / Q000378:metabolism; D016027:Heart Transplantation / Q000379:methods*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009566:Nitrates / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009573:Nitrites / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D013859:Thiocarbamates / Q000008:administration & dosage* / Q000737:chemistry; D014184:Transplantation, Homologous
chemical_list: D009566:Nitrates; D009573:Nitrites; D013859:Thiocarbamates; D009569:Nitric Oxide