Apoptosis and Increased Expression of Inducible Nitric Oxide Synthase in Human Allograft Rejection1

Szabolcs, Matthias; Ravalli, Stefano; Minanov, Oktavijan P.; Sciacca, Robert R.; Michler, Robert E.; Cannon, Paul J.

doi:10.1097/00007890-199803270-00007

Cited by 131 publications

(61 citation statements)

References 43 publications

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“…23 Apoptosis of cardiac myocytes and of infiltrating macrophages has also been observed in parallel with the upregulation of iNOS mRNA, protein, and enzyme activity in rejecting rat cardiac allografts and in human endomyocardial biopsies from hearts undergoing class 3 (ISHLT) rejection. 18,48 These associations, along with in vitro studies of NO-mediated cardiomyocyte apoptosis, have suggested that NO may be an apoptotic trigger in this situation. 49,50 The slight reductions observed in apoptotic cell numbers in the animals treated with the COX-2 and iNOS inhibitors were not statistically significant.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of COX-2 During Cardiac Allograft Rejection

Yang

Szabolcs

et al. 2000

Circulation

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Background-The hypothesis that cyclooxygenase-2 (COX-2) is involved in the myocardial inflammatory response during cardiac allograft rejection was investigated using a rat heterotopic abdominal cardiac transplantation model. Methods and Results-COX-2 mRNA and protein in the myocardium of rejecting cardiac allografts were significantly elevated 3 to 5 days after transplantation compared with syngeneic controls (nϭ3, PϽ0.05). COX-2 upregulation paralleled in time and extent the upregulation of iNOS mRNA, protein, and enzyme activity in this model. COX-2 immunostaining was prominent in macrophages infiltrating the rejecting allografts and in damaged cardiac myocytes. Prostaglandin (PG) levels in rejecting allografts were also higher than in native hearts. Because NO has been reported to modulate PG synthesis by COX-2, additional transplants were performed using animals treated with a selective COX-2 inhibitor (SC-58125) and a selective inhibitor of the inducible nitric oxide synthase (iNOS) N-aminomethyl-L-lysine. At posttransplant day 5, inhibitor administration resulted in a significant reduction of COX-2 mRNA expression (3764Ϯ337 versus 5110Ϯ141 arbitrary units, nϭ3, PϽ0.05) and iNOS enzymatic activity (1.7Ϯ0.4 versus 22.8Ϯ14.4 nmol/mg protein, nϭ3, PϽ0.01) compared with vehicle-treated allogeneic transplants. Allograft survival in treated animals was increased modestly from 5.4 to 6.4 days (PϽ0.05). However, apoptosis of cardiac myocytes (TUNNEL method) was only marginally reduced relative to vehicle controls in treated graft recipients. The intensity of allograft rejection was also similar in the treated and untreated allografts. Conclusions-The data indicates that COX-2 expression is enhanced in parallel with iNOS in the myocardium during cardiac allograft rejection. (Circulation. 2000;101:430-438.)

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Section: Discussionmentioning

confidence: 99%

Upregulation of COX-2 During Cardiac Allograft Rejection

Yang

Szabolcs

et al. 2000

Circulation

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“…Furthermore, in human cardiac transplantation, evidence of increased apoptosis was more likely to be associated with increased cardiac dysfunction (Birks et al, 2000). Clinically, the importance of peroxynitrite formation was also suggested from previous studies showing increased immunostaining for nitrotyrosine in biopsies of human cardiac grafts with grade III rejection scores but not in biopsies with grade 0 histological rejection scores (Szabolcs et al, 1998). In a recent study, we have shown that neutralizing NO directly limits the extent of protein nitration in rat cardiac transplants and prolongs graft survival (Pieper et al, 2004).…”

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confidence: 85%

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.

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“…Besides above mentioned studies which in part have been performed in human cells it appears that apoptosis, iNOS induction, and human cardiac allograft rejection and/or chronic heart failure are positively correlated. It is assumed that iNOS in macrophages or mycocytes is involved in regulating apoptosis 64,65 in close analogy to iNOS expression and apoptosis in human vascular smooth muscle cells. 44 Furthermore, the appearance of p53 and iNOS in apoptotic macrophages is established in human atherosclerotic lesions.…”

Section: Lessons From Disease Statesmentioning

confidence: 99%

Nitric oxide (NO): an effector of apoptosis

1999

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It is appreciated that the production of nitric oxide (NO) from Larginine metabolism is an essential determinate of the innate immune system, important for nonspecific host defense, as well as tumor and pathogen killing. Cytotoxicity as a result of a substantial NO-formation is established to initiate apoptosis, characterized by upregulation of the tumor suppressor p53, changes in the expression of pro-and anti-apoptotic Bcl-2 family members, cytochrome c relocation, activation of caspases, chromatin condensation, and DNA fragmentation. Proof for the involvement of NO was demonstrated by blocking adverse effects by NO-synthase inhibition. However, NOtoxicity is not a constant value and NO may achieve cell protection as well. In part this is understood by transcription and translation of protective proteins, such as cyclooxygenase-2. Alternatively, protection may result as a consequence of a diffusion controlled NO/O 2 7 (superoxide) interaction that redirects the apoptotic initiating activity of NO towards protection. NO is endowed with the unique ability to initiate and to block apoptosis, depending on multiple variables that exist to be elucidated. The crosstalk between cell destructive and protective signaling pathways under the modulatory influence of NO will determine the impact of NO in apoptotic cell death and survival.

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Apoptosis and Increased Expression of Inducible Nitric Oxide Synthase in Human Allograft Rejection1

Abstract: Apoptosis is a major form of myocyte death during human cardiac allograft rejection. Cardiac myocyte apoptosis is closely associated with expression of iNOS in macrophages and myocytes and with nitration of myocyte proteins by peroxynitrite.

Cited by 131 publications

References 43 publications

Upregulation of COX-2 During Cardiac Allograft Rejection

Upregulation of COX-2 During Cardiac Allograft Rejection

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

Nitric oxide (NO): an effector of apoptosis

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