Myocardial Nuclear Factor-??B Activity and Nitric Oxide Production in Rejecting Cardiac Allografts1

Cooper, Matthew M.; Lindholm, Paul F.; Pieper, Galen M.; Seibel, Ross; Moore, Gail; Nakanishi, Akemi; Dembny, Kenneth; Komorowski, Richard; Johnson, Christopher P.; Adams, Mark B.; Roza, Allan M.

doi:10.1097/00007890-199810150-00005

Cited by 62 publications

(46 citation statements)

References 28 publications

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“…Furthermore, spintrapping studies showed definitive evidence that the loss of an atom of Fe in purified aconitase serves as a source of hydroxyl radical formation (30). These findings are interesting considering the previous benefits on graft survival associated with treatment with a hydroxyl radical scavenger, dimethylthiourea, or the metal chelator, pyrrolidine dithiocarbamate (11,31). These studies indicate that the molecular alteration in activity of the native aconitase enzyme with the loss of a reactive metal ion may have a significant affect on cell respiration and production of cell injury.…”

Section: Discussionmentioning

confidence: 78%

“…In contrast, in the setting of excess NO production via iNOS, it is possible that molecular interactions of NO with iron-containing proteins may lead to altered cell function or cell injury. Indeed, nitrosylation of heme protein (notably myoglobin) has been demonstrated by EPR spectroscopy in acute cardiac allograft rejection (10)(11)(12). EPR signals for nitrosylated heme protein are found in allograft tissue but not isograft tissue, suggesting that the increase in nitrosylation is due to alloimmune activation rather than secondarily to artifacts of surgery.…”

mentioning

confidence: 99%

“…The cause-effect relationship in nitrosylation of heme protein on graft function during rejection is incompletely understood. Nevertheless, intervention with NOS inhibitors (11,12) or NO scavengers (5-7) that decreased heme nitrosylation also decreased histological rejection scores and prolonged graft survival.…”

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confidence: 99%

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Non-heme iron protein: A potential target of nitric oxide in acute cardiac allograft rejection

Pieper

Halligan

Hilton

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 78%

mentioning

confidence: 99%

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Non-heme iron protein: A potential target of nitric oxide in acute cardiac allograft rejection

Pieper

Halligan

Hilton

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…In the first experiment, pyrrolidine dithiocarbamate, an iron-chelator, prolonged grafts survival and inhibited down-stream effects on nitrosylation of myocardial heme protein [48,49]. While this agent inhibited NF-κB binding activity, it was not determined whether the decreased heme protein nitrosylation was due secondarily to NO scavenging or to decreased iNOS protein expression.…”

Section: Evidence Using No Neutralizing Agentsmentioning

confidence: 99%

The complex role of iNOS in acutely rejecting cardiac transplants

Pieper

Roza

2008

Free Radical Biology and Medicine

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This review summarizes the evidence for a detrimental role of nitric oxide (NO) derived from inducible NO synthase (iNOS) and/or reactive nitrogen species such as peroxynitrite in acutelyrejecting cardiac transplants. In chronic cardiac transplant rejection, iNOS may have an opposing beneficial component. The purpose of this review is primarily to address issues related to acute rejection which is a recognized risk factor for chronic rejection. The evidence for a detrimental role is based upon strategies involving non-selective NOS inhibitors, NO neutralizers, selective iNOS inhibitors and iNOS gene deletion in rodent models of cardiac rejection. The review is discussed in the context of the impact on various components including graft survival, histological rejection and cardiac function which may contribute in toto to the process of graft rejection. Possible limitations of each strategy are discussed in order to understand better the variance in published findings including issues related to the potential importance of cell localization of iNOS expression. Finally, the concept of a dual role of NO and its down-stream product, peroxynitrite, in rejection vs. immune regulation is discussed.

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“…However, administration of pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of NFkB, markedly prolonged graft survival with a decreased peak of NFkB activity in this model. 15 The immunosuppressive agents FK506 and cyclosporin A (CsA) are reported to switch off gene transcription by inhibiting a key signaling phosphatase, calcinurin, which is involved in the activation of NFkB. [16][17][18] Glucocorticoid, another major immunosuppressive agent, is also believed to work partly via inhibition of NFkB activation.…”

Section: Introductionmentioning

confidence: 99%

Transfection of NFκB-decoy oligodeoxynucleotides using efficient ultrasound-mediated gene transfer into donor kidneys prolonged survival of rat renal allografts

et al. 2003

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Nuclear factor kB (NFkB) plays a pivotal role in the coordinated transactivation of a series of genes of cytokines and adhesion molecules that are highly involved in the onset of acute rejection in organ transplantation. We previously developed decoy cis-elements oligo deoxyribonucleic acid against NFkB (NFkB-decoy) that effectively inhibited the activation of major inflammatory mediators in vitro and in vivo. Accordingly, we hypothesized that transfection of NFkB-decoy into the donor kidney would prevent acute rejection and prolong graft survival, and thus provide effective therapy for renal acute rejection. To transfect NFkB-decoy, we employed a novel approach using ultrasound exposure with an echocardiographic contrast agent, Optison, and clearly demonstrated successful transfection of NFkB-decoy into renal tissue. The therapeutic effect of NFkB-decoy on renal allografts was then evaluated in a rat renal allograft model (Wistar-Lewis). In the control group, graft function significantly deteriorated with marked destruction of renal tissue, accompanied by increased production of major inflammatory mediators, and all animals died of renal failure by 9 days. In contrast, graft function (serum creatinine on day 2, NFkB-treated: 0.9770.16 versus control: 1.8470.23 mg/dl, Po0.01) and histological structure were well preserved with significantly decreased expression of NFkB-regulated cytokines and adhesion molecules, including IL-1, iNOS, MCP-1, TNF-a, and ICAM-1, in allografts transfected with NFkB-decoy. As a result, animal survival was significantly prolonged in this group as compared to controls (14.275.2 versus 7.171.2 days, Po0.01). Thus, we established a novel ultrasound-Optison-mediated gene transfection approach and demonstrated the significant prolongation of graft survival by the successful transfection of NFkB-decoy into the donor kidney in a rat renal allograft model. Gene Therapy (2003) 10, 415-425.

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Myocardial Nuclear Factor-??B Activity and Nitric Oxide Production in Rejecting Cardiac Allografts1

Abstract: These data support a role for NF-kappaB in allograft rejection.

Cited by 62 publications

References 28 publications

Non-heme iron protein: A potential target of nitric oxide in acute cardiac allograft rejection

Non-heme iron protein: A potential target of nitric oxide in acute cardiac allograft rejection

The complex role of iNOS in acutely rejecting cardiac transplants

Transfection of NFκB-decoy oligodeoxynucleotides using efficient ultrasound-mediated gene transfer into donor kidneys prolonged survival of rat renal allografts

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