Effects of Inhibition of Poly(Adenosine Diphosphate-Ribose) Synthase on Acute Cardiac Allograft Rejection

Liu, Yulin; Son, Ni Huiping; Szabolcs, Matthias; Ma, Ninsheng; Sciacca, Robert R.; Albala, Arline; Edwards, Niloo M.; Cannon, Paul J.

doi:10.1097/01.tp.0000131662.01491.2e

Cited by 12 publications

(16 citation statements)

References 24 publications

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“…The observation that 5-aminoisoquinoline, an inhibitor of PARP, attenuated rejection scores and improved graft survival in a rodent model of cardiac allograft rejection suggests the importance of PARP activation (Liu et al, 2004). In our study, we found that WW85 given alone decreased poly(ADP-ribose), suggesting that it acted, in part, by decreasing PARP activation.…”

supporting

confidence: 54%

“…PARP activation has been shown after reperfusion injury in rat cardiac transplants or following alloimmune activation and rejection in rat tracheal (Farivar et al, 2004) and cardiac (Liu et al, 2004) allografts. The observation that 5-aminoisoquinoline, an inhibitor of PARP, attenuated rejection scores and improved graft survival in a rodent model of cardiac allograft rejection suggests the importance of PARP activation (Liu et al, 2004).…”

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confidence: 99%

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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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supporting

confidence: 54%

mentioning

confidence: 99%

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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“…The cardiac protective effect of PARP inhibitors was subsequently extended into various models of heart transplantation. Treatment of the recipients with PARP inhibitors resulted in improved myocardial contractility and longer survival time of the transplanted hearts (Fiorillo et al, 2002(Fiorillo et al, , 2003Szabó et al, 2002Szabó et al, , 2005Szabó et al, , 2006Liu et al, 2004;Gao et al, 2007). The mode of action of PARP inhibitors, as cardioprotective agents, appears to involve a combination of mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats

Korkmaz‐Icöz

Szczesny

Marcatti

et al. 2017

British J Pharmacology

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*Equally contributed. BACKGROUND AND PURPOSEOlaparib, rucaparib and niraparib, potent inhibitors of poly(ADP-ribose) polymerase (PARP) are approved as anti-cancer drugs in humans. Considering the previously demonstrated role of PARP in various forms of acute and chronic myocardial injury, we tested the effects of olaparib in in-vitro models of oxidative stress in cardiomyocytes, and in an in vivo model of cardiac transplantation. EXPERIMENTAL APPROACHH9c2-embryonic rat heart-derived myoblasts pretreated with vehicle or olaparib (10μM) were challenged with either hydrogen peroxide (H 2 O 2 ) or with glucose oxidase (GOx, which generates H 2 O 2 in the tissue culture medium). Cell viability assays (MTT, lactate dehydrogenase) and Western blotting for PARP and its product, PAR was performed. Heterotopic heart transplantation was performed in Lewis rats; recipients were treated either with vehicle or olaparib (10 mg kg -1 ). Left ventricular function of transplanted hearts was monitored via a Millar catheter. Multiple gene expression in the graft was measured by qPCR. KEY RESULTSOlaparib blocked autoPARylation of PARP1 and attenuated the rapid onset of death in H9c2 cells, induced by H 2 O 2 , but did not affect cell death following chronic, prolonged oxidative stress induced by GOx. In rats, after transplantation, left ventricular systolic and diastolic function were improved by olaparib. In the transplanted hearts, olaparib also reduced gene expression for c-jun, caspase-12, catalase, and NADPH oxidase-2. CONCLUSIONS AND IMPLICATIONSOlaparib protected cardiomyocytes against oxidative stress and improved graft contractility in a rat model of heart transplantation. These findings raise the possibility of repurposing this clinically approved oncology drug, to be used in heart transplantation. LINKED ARTICLES

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“…Therapeutic interventions that are shown to decrease nitrotyrosine formation in cardiac myocytes per se have, in general, also been shown to increase graft survival or inhibit histological rejection [52,129,130]. In studies using a COX-2 inhibitor, graft survival was prolonged with weak staining for nitrotyrosine which was confined to inflammatory cells [129].…”

Section: Cell Localization Of Nitrationmentioning

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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Effects of Inhibition of Poly(Adenosine Diphosphate-Ribose) Synthase on Acute Cardiac Allograft Rejection

Cited by 12 publications

References 24 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

Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats

The complex role of iNOS in acutely rejecting cardiac transplants

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