Acute Cardiac Allograft Rejection in Nitric Oxide Synthase-2
            <sup>−/−</sup>
            and Nitric Oxide Synthase-2
            <sup>+/+</sup>
            Mice

Szabolcs, Matthias; Ma, Ninsheng; Athan, E; Zhong, Jing; Ming, Ming; Sciacca, Robert R.; Husemann, Jens; Albala, Arline; Cannon, Paul J.

doi:10.1161/01.cir.103.20.2514

Cited by 43 publications

(15 citation statements)

References 17 publications

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“…Since this intervention also decreased iNOS expression, it is possible that decreased nitration resulted secondarily from decreased production of NO, a substrate for peroxynitrite formation. Other studies from the same group using iNOS knockout mice showed decreased apoptosis and lack of nitrotyrosine formation when iNOS Ϫ/Ϫ donor and recipients were used compared with presence of nitrotyrosine when iNOS ϩ/ϩ allografts were used (Szabolcs et al, 2001). These findings are complemented by our studies showing that limitation of NO by two mechanisms, by inhibiting iNOS activity but not expression and decreasing iNOS expression by immunosuppressant therapy, both decreased protein nitration (Pieper et al, 2004).…”

Section: Discussionsupporting

confidence: 75%

Protective Mechanisms of a Metalloporphyrinic Peroxynitrite Decomposition Catalyst, WW85, in Rat Cardiac Transplants

Pieper¹,

Nilakantan²,

Chen³

et al. 2005

J Pharmacol Exp Ther

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Nitric oxide (NO) derived from inducible NO synthase has been implicated in cardiac rejection. However, little is known about the role of the reactive nitrogen species peroxynitrite. We examined the protective actions of a peroxynitrite decomposition catalyst, WW85, in an experimental model of acute cardiac rejection. Heterotopic, abdominal transplantation of rat donor hearts was performed. Groups included isografts, allografts, or allografts treated with WW85, cyclosporine, or cyclosporine ϩ WW85. We determined graft survival, histological rejection, and graft function (by in situ sonomicrometry). Intragraft biochemical analysis of cytokines and proapoptotic and antiapoptotic gene expression using reverse transcriptase-polymerase chain reaction were determined. Treatment with WW85 or cyclosporine alone prolonged graft survival, improved graft function, and decreased histological rejection. Graft survival was further significantly (P Ͻ 0.001) enhanced by combination treatment. A decrease was also shown in nitrotyrosine, poly(ADP-ribose) polymerase (PARP) activation, and lipid peroxide formation by WW85 that was potentiated when given in combination with cyclosporine. Benefits could not be ascribed to changes in intragraft myeloperoxidase activity. Only combination therapy produced significant decreases in inflammatory cytokine gene expression, suggesting that WW85 acted primarily downstream of these stimuli. In general, WW85 had no direct action on expression of the proapoptotic gene, Fas ligand; however, WW85 given alone or with cyclosporine enhanced expression of antiapoptotic genes Bcl-2 and Bcl-xL. Collectively, these findings suggest a protective action of the peroxynitrite decomposition catalyst WW85 on graft rejection that is independent of any action on leukocyte sequestration and cytokine gene expression. Rather, effects seem to be downstream on decreased protein nitration, decreased lipid peroxidation, and decreased PARP activation.

show abstract

Section: Discussionsupporting

confidence: 75%

Protective Mechanisms of a Metalloporphyrinic Peroxynitrite Decomposition Catalyst, WW85, in Rat Cardiac Transplants

Pieper¹,

Nilakantan²,

Chen³

et al. 2005

J Pharmacol Exp Ther

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“…This finding agreed with previous studies showing inhibition of nitration using other selective iNOS inhibitors [64,127]. Finally, the role of iNOS in nitrotyrosine formation was firmly established in mouse heart transplants using genetic ablation of iNOS [73].…”

Section: Pathways Of Protein Nitration In Cardiac Rejectionsupporting

confidence: 91%

“…That nitration of cardiac grafts arises specifically from iNOS was clear in studies conducted in iNOS −/− and wild-type mice. Nitrotyrosine was present when either donor or recipient was iNOS positive; however, nitrotyrosine was absent when iNOS −/− donor hearts were transplanted into iNOS −/− recipient mice [73].…”

Section: Cell Localization Of Nitrationmentioning

confidence: 96%

“…In a 3 rd more recent study (illustrated in Figure 2), Szabolcs et al [73] showed in an initial strategy that there was no difference in graft survival time or ISHLT rejection scores for donor hearts transplanted into iNOS −/− and iNOS +/+ recipient mice. Similar findings were obtained in a second strategy if iNOS −/− and iNOS +/+ donor hearts were transplanted into the same iNOS +/+ strain allograft recipients.…”

Section: Evidence Using Gene Deletion Strategiesmentioning

confidence: 99%

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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, in a rat cardiac allograft model, L-NIL was able to prolong allograft survival from 7 to ϳ10 days under certain conditions (11). Also work with iNOS knockout (iNOS Ϫ/Ϫ involvement of inducible NO formation in rejection was observed (12), whereas in another more recent study where recipients and donor hearts were from iNOS Ϫ/Ϫ mice, participation of iNOS in the inflammatory response leading to rejection was demonstrated (13). Furthermore, participation of iNOS in developing cardiac allograft vasculopathy in the course of chronic rejection has been shown (14).…”

mentioning

confidence: 97%

Tetrahydro-4-Aminobiopterin Attenuates Dendritic Cell-Induced T Cell Priming Independently from Inducible Nitric Oxide Synthase

Thoeni

Stoitzner

Brandacher

et al. 2005

The Journal of Immunology

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Formation of NO by NO synthases (NOSs) strictly depends on tetrahydrobiopterin. Its structural analog, tetrahydro-4-aminobiopterin, is an inhibitor of all NOS isoenzymes, which prolongs allograft survival in acute murine cardiac rejection and prevents septic shock in the rat. In this study, we show that murine bone marrow-derived dendritic cells treated with tetrahydro-4-aminobiopterin had a reduced capacity to prime alloreactive murine T cells in oxidative mitogenesis. Checking for a possible influence on LPS-induced dendritic cell maturation, we found that tetrahydro-4-aminobiopterin down-regulated MHC class II expression and counteracted LPS-induced down-regulation of ICOS ligand, while expression of CD40, CD86, CD80, B7-H1, and B7-DC remained unchanged. Tetrahydro-4-aminobiopterin also reduced activation of CD4+ T cells isolated from mice overexpressing an OVA-specific TCR by OVA-loaded murine bone marrow-derived dendritic cells, thus indicating that its effect on MHC class II expression is involved in attenuating T cell activation. In line with affecting dendritic cell function and T cell activation, tetrahydro-4-aminobiopterin impaired production of proinflammatory cytokines and the Th1 response. With regard to cell survival, tetrahydro-4-aminobiopterin induced efficient apoptosis of murine T cells but not of murine dendritic cells. Experiments with cells from inducible NOS (iNOS) knockout mice and with N6-(1-iminoethyl)-l-lysine, a specific inhibitor of iNOS, ruled out participation of iNOS in any of the observed effects. These findings characterize attenuation of T cell stimulatory capacity of murine bone marrow-derived dendritic cells as an immunosuppressive mechanism of tetrahydro-4-aminobiopterin that is not related to its iNOS-inhibiting properties.

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Acute Cardiac Allograft Rejection in Nitric Oxide Synthase-2 ^−/− and Nitric Oxide Synthase-2 ^+/+ Mice

Abstract: The data suggest that NO derived from NOS-2 contributes to the inflammatory response and to cardiomyocyte damage and apoptosis during acute cardiac allograft rejection.

Cited by 43 publications

References 17 publications

Protective Mechanisms of a Metalloporphyrinic Peroxynitrite Decomposition Catalyst, WW85, in Rat Cardiac Transplants

Protective Mechanisms of a Metalloporphyrinic Peroxynitrite Decomposition Catalyst, WW85, in Rat Cardiac Transplants

The complex role of iNOS in acutely rejecting cardiac transplants

Tetrahydro-4-Aminobiopterin Attenuates Dendritic Cell-Induced T Cell Priming Independently from Inducible Nitric Oxide Synthase

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Acute Cardiac Allograft Rejection in Nitric Oxide Synthase-2 −/− and Nitric Oxide Synthase-2 +/+ Mice

Abstract: The data suggest that NO derived from NOS-2 contributes to the inflammatory response and to cardiomyocyte damage and apoptosis during acute cardiac allograft rejection.

Cited by 43 publications

References 17 publications

Protective Mechanisms of a Metalloporphyrinic Peroxynitrite Decomposition Catalyst, WW85, in Rat Cardiac Transplants

Protective Mechanisms of a Metalloporphyrinic Peroxynitrite Decomposition Catalyst, WW85, in Rat Cardiac Transplants

The complex role of iNOS in acutely rejecting cardiac transplants

Tetrahydro-4-Aminobiopterin Attenuates Dendritic Cell-Induced T Cell Priming Independently from Inducible Nitric Oxide Synthase

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Resources

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Acute Cardiac Allograft Rejection in Nitric Oxide Synthase-2 ^−/− and Nitric Oxide Synthase-2 ^+/+ Mice