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Ann Thorac Surg 2005;80:950-956
© 2005 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Poly (ADP) Ribose Polymerase Inhibition Improves Rat Cardiac Allograft Survival

^a University of Washington Medical Center, Department of Surgery, Division of Cardiothoracic Surgery, Seattle, Washington
^b Inotek Pharmaceuticals Corp, Beverly, Massachusetts

Accepted for publication February 7, 2005.

^_* Address reprint requests to Dr Mulligan, Department of Cardiothoracic Surgery, Box 356310, University of Washington Medical Center, 1959 NE Pacific St, Seattle, WA 98195 (Email: msmmd{at}u.washington.edu).

	Abstract

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BACKGROUND: Heart transplantation is an accepted treatment modality for end-stage heart failure. However, acute cellular rejection (ACR) continues to be a morbid complication. Recently a novel mechanism of inflammatory allograft injury has been characterized which involves overactivation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP). In the present studies, we compared the efficacy of INO-1001, a novel, potent PARP inhibitor, in limiting ACR with and without adjuvant low-dose cyclosporine (CSA).

METHODS: Heterotopic heart transplantation was performed utilizing Brown-Norway strains as donors and Lewis rats as recipients. Groups received daily intraperitoneal injections of: vehicle, low-dose CSA, low-dose INO-1001, high-dose INO-1001, and low-dose CSA combined with high-dose INO-1001. Additional animals were sacrificed on postoperative Day 5 for histologic assessments of allograft inflammation, including immunohistochemistry for nitrotyrosine and poly (ADP-ribose) (the product of PARP) staining.

RESULTS: PARP inhibition significantly prolonged allograft survival relative to vehicle controls. The combination of low-dose CSA and INO-1001 resulted in a marked increase in allograft survival and significant reductions in allograft rejection scores. This was associated with decreased nitrotyrosine and PAR staining in transplanted cardiac allografts.

CONCLUSIONS: Pharmacologic inhibition of INO-1001 prolongs allograft survival in a dose-dependent fashion in a rodent model of heart transplantation. PARP inhibitors may permit reductions in the dose of CSA needed for adequate immunosuppression after heart transplantation.

	Introduction

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Drs Chen, Jagtap, and Szabó disclose that they have a financial relationship with Inotek Pharmaceuticals, Corp.

 

Heart transplantation is now well accepted as a viable treatment modality for patients with end-stage heart failure or intractable coronary artery disease. The registry for the International Society for Heart and Lung Transplantation lists the 1- and 5-year survival rates for heart transplant recipients as 89% and 71%, respectively [1]. However, acute cellular rejection (ACR) continues to be a morbid complication affecting these patients, contributing to decreased quality of life, increased healthcare costs, and higher mortality rates [2].

Acute cellular rejection is a challenging problem for clinicians, and the major impediment to the clinical translation of xenotransplantation [3]. Pathologically, acutely rejecting allografts demonstrate endothelial monolayer disruption, ischemia, and intravascular coagulation. Although it is classically believed that antidonor antibodies against major histocompatibility complex (MHC) antigens drive this process, there are other factors that contribute to tissue injury in the early post-transplant period. Myocardial ischemia-reperfusion (IR) injury, an inevitable consequence of cardiac transplanatation, is known to generate highly toxic nitrogen and oxygen derived free radicals, to activate endothelial cells, platelets, and macrophages, and to upregulate cytokine and chemokine gene expression [4]. These events result in endothelial permeability, activation of the complement pathway, and recruitment of inflammatory cells to the allograft inducing tissue injury and enhancing the effects of allograft rejection. Given the lack of significant improvements in reducing ACR and improving survival in this cohort of patients over the past decade, it is likely that there are uncharacterized synergistic pathways, untreated by our current immunosuppressive regimens, which promote allograft injury.

Allograft reperfusion generates oxygen and nitrogen derived free radicals, such as superoxide anion and nitric oxide, which combine to form a highly reactive molecule termed peroxynitrite [5]. Peroxynitrite is genotoxic, inducing DNA base modifications and single-stranded DNA breaks. Poly (ADP-ribose) polymerase (PARP) is an abundant nuclear enzyme, and is present in most eukaryotic cells including cardiomyocytes. Under normal circumstances, PARP is believed to promote DNA repair [6]. However, in response to DNA injury from oxidative or nitrosative stress, PARP becomes overactivated, leading to depletion of intracellular stores of NAD⁺ and ATP [6]. Because both are involved in mitochondrial respiration and glycolysis, depletion of these factors results in deranged cellular energetics and eventual cell death [6]. PARP activation also promotes the mitochondrial release of various cell death factors, and is involved in the upregulation of a variety of pro-inflammatory genes and gene products including cytokines and chemokines. PARP activation can also promote the infiltration of mononuclear cells into inflammatory sites [6].

At the initiation of the present project, it was unknown whether PARP was involved in the tissue injury associated with ACR of cardiac allografts. One study has been published recently, which used an early-generation PARP inhibitor, 3-aminobenzamide (3-AB), in an experimental model of IR injury in heart transplantation [7]. These data suggested that PARP activation promotes tissue injury in this model, as 3-AB markedly attenuated lipid peroxidation and the depletion of NAD⁺ and ATP in transplanted rat hearts early in reperfusion. However, 3-aminobenzamide also reduced DNA strand breakage, which is consistent with its non-specific antioxidant effects (see [8] for review on the pharmacological effects and side effects of various PARP inhibitor compounds). In addition, in this study, effects on graft survival were not assessed, indeed the effects of PARP inhibition beyond 60 minutes of reperfusion were not studied. In the present study, we have utilized a newer generation, potent PARP inhibitor termed INO-1001 [9–12] in a rat model of cardiac transplantation. A key issue investigated in the current study was to determine whether PARP inhibition works in an additive or synergistic fashion with low dose immunosuppression (cyclosporine A). We have followed a range of histological and biochemical parameters, and we have also followed the activation of PARP, via immunohistochemical detection of poly (ADP-ribose) (PAR), the enzymatic product of activated PARP [6]. An additional aim of the study was to evaluate whether our interventions influence the myocardial production of peroxynitrite, a reactive cardiotoxic oxidant [5]. This evaluation was conducted via immunohistochemical detection of nitrotyrosine, a protein modification characteristic to the reactivity of peroxynitrite.

	Material and Methods

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Reagents
All reagents were purchased from Sigma Chemical (St. Louis, MO) unless otherwise specified. For inhibition of PARP, we have used INO-1001, a novel, isoindolinone-based PARP inhibitor compound, with PARP inhibitory effects in the nanomolar-low micromolar range in cell-based PARP activity assays [9–13].

Donor Procedure
Heart transplantation procedures were conducted according to previously described and validated methods and principles [14, 15]. Brown-Norway rats, weighing approximately 250 grams, were sedated with pentobarbital given via the intraperitoneal (IP) route at a dosage of 120 mg/kg. A Zeiss S3 Universal operating microscope (Carl Zeiss Inc, Thornwood, NY) was used for both explantation and implantation. A tracheostomy was performed and animals ventilated on a Harvard Rodent Ventilator (Harvard Apparatus, South Natick, MA), model 683, at an inspired O₂ content of 60%, PEEP of 2 cm H₂O, rate of 80 breaths/min, and tidal volume of 10 mL/kg. After a median sternotomy was performed and a chest retractor placed, 4–0 silk ties were placed around both superior vena cavae, brachiocephalic artery, and the inferior vena cava (IVC). An additional tie was placed through the transverse sinus and around all cavae so as to occlude the pulmonary veins. Heparin was then administered (50 units), and all ties were ligated except the ones in the transverse sinus and IVC. The ventilator was shut off and cold cardioplegic flush initiated after a venotomy in the IVC was created. Cold slush was placed in the chest. After the flush was concluded, the IVC tie, followed by the transverse sinus tie, was ligated in that order. The aorta and pulmonary artery were transected, the heart removed from other mediastinal structures, and placed in cold saline until implantation.

Recipient Procedure
Lewis rats weighing approximately 250 grams were anesthetized with IP ketamine at a dose of 120 mg/kg. A laparotomy was performed and two ties placed around the abdominal aorta and IVC. A clamp was subsequently placed on these two structures and a venotomy performed for anastomosis of the donor PA to recipient IVC using 8-0 prolene in a running fashion. Subsequently the donor aorta was anastomosed to the recipient abdominal aorta in an end-to-side fashion using 8-0 suture. At the conclusion of the procedure, the clamp was removed and the heart allowed to reperfuse. Total ischemic time (both cold and warm) was less than 30 minutes for all cases, and all transplants were done by the same operator (A.F.). A Brown-Norway and Lewis combination was chosen for these procedures as it represents a complete MHC mismatch.

Allograft Survival Studies
Allograft viability was monitored daily by palpation. Terminal rejection was defined by cessation of a palpable heartbeat, which was later confirmed by histology. Five groups were studied in total: vehicle-treated positive controls, low dose INO-1001 (3 mg/kg/day), high dose INO-1001 (30 mg/kg/day), low dose CSA (2.5 mg/kg/day), and high dose INO-1001 (30 mg/kg/day) combined with low dose CSA (2.5 mg/kg/day). All reagents were administered once daily via the intraperitoneal route, and grafts were checked by the same individual every morning.

Allograft Tissue Studies
Additional animals were transplanted for tissue molecular studies, and were divided into the same groups as listed above. Each group contained at least four animals. Given that the positive controls rejected by Day 7 on average, allografts were harvested on Day 5 to standardize histologic comparisons between experimental groups. After sedating the animals with a lethal dose of IP pentobarbital, the transplanted heart was explanted. The heart was incised with a scalpel along the septal plane, and half was placed in 10% neutral buffered formalin, and the other half placed in liquid nitrogen. All specimens, except those in formalin, were stored immediately in a –80°C freezer.

Immunohistochemistry for Par and Nitrotyrosine
Tissue sections were deparaffinized and rehydrated by passing through Safeclear II (Fisher Scientific, Pittsburgh, PA) and a graded series of ethanol baths. Antigen retrieval was performed for 20 minutes in sodium citrate buffer, pH 6.4, in a microwave oven. Endogenous peroxidase activity was blocked by incubating the sections in 0.3% hydrogen peroxide for 15 minutes. After 30 minutes of incubation in normal goat serum, tissue sections were incubated overnight with rabbit polyclonal antibody against poly (ADP-ribose) (1:250; Tulip BioLabs, Inc, West Point, PA) or rabbit polyclonal antibody against nitrotyrosine (2.5 µg/mL; Upstate Group, Waltham, MA), and then incubated with biotinylated secondary antibody and avidin-biotin-peroxidase complex kit (Vector Laboratories, Burlingame, CA). Color was developed using Ni-diaminobenzidine. The section was counterstained with nuclear fast red for PARP staining or hematoxylin for nitrotyrosine staining [13].

Semiquantitative Grade of ACR
An experienced pathologist, blinded to the identity of the experimental groups, evaluated and scored hematoxilyn and eosin stained sections of allografts from various groups, using a semiquantitative scale for myocyte loss and degree of inflammation (corresponding to ISHLT rejection grades in human allografts). We utilized a scale in which 0 indicates no inflammation and myocyte loss (ISHLT grade 0); 1, perivascular inflammation (ISHLT grade 1A); 2, interstitial inflammation (ISHLT grade 1B); 3, inflammation with focal myocyte loss (ISHLT grade 2); 4, inflammation with multifocal myocyte loss (ISHLT grade 3A); 5, inflammation with confluent foci of myocyte loss (ISHLT grade 3B); and 6, inflammation with large areas of necrosis (>25% myocyte loss) and/or necrotizing vasculitis (ISHLT grade 4).

Statistics
All data are presented as mean ± standard error of mean unless noted. One-way analysis of variance (ANOVA) determined if statistically significant differences were present between groups for the allograft viability studies, with a post-hoc Bonferroni modification for multiple comparisons. Student’s t tests were used to compare individual groups after ANOVA analysis.

	Results

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Allograft Survival
Table 1 summarizes the results for allograft survival in the different experimental groups. Survival was significantly prolonged by INO-1001 in a dose-dependent fashion relative to vehicle controls. However, the use of INO-1001, even at high doses, was not as efficacious at limiting ACR as was low-dose CSA. When low-dose CSA was combined with high-dose INO-1001, both allograft inflammation and ACR were limited in dramatic fashion, and allografts were viable to an average of 66 days. Not only did this combination therapy confer statistically significant greater levels of protection than vehicle treatment, but there was clearly a benefit to adding INO-1001 to low-dose CSA, when compared to low-dose CSA alone.

View larger version (132K): [in this window] [in a new window]   Fig 1. Allograft histology at posttransplant Day 5 is illustrated. (A) A hemotoxylin-eosin stained section of a vehicle-treated allograft, demonstrating marked interstitial edema, infiltration by inflammatory cells, and cardiomyocyte necrosis. The modified rejection score of this group averaged 5.5. (B) Panel B is an allograft treated with the combination regimen of low-dose cyclosporine and the PARS inhibitor INO-1001. There are dramatically less inflammatory cells and myocyte necrosis compared to the vehicle group, and the architecture appears well preserved. (INO-1001 = poly [ADP-ribose] polymerase inhibitor; PAR = poly [ADP] ribose.)

View larger version (171K): [in this window] [in a new window]   Fig 2. Immunohistochemical PAR staining in: (A) myocardial sections treated with vehicle, (B) high-dose INO-1001, (C) low-dose cyclosporine, and (D) combination of low-dose cyclosporine and high-dose INO-1001. Nuclei of necrotic cardiomyocytes and infiltrated inflammatory cells displayed strong immunostaining for PAR in vehicle, high-dose INO-1001 or low-dose cyclosporine-treated sections. The numbers of PAR-positive nuclei was markedly less in sections treated with the combination of low-dose cyclosporine and high-dose INO-1001. (INO-1001 = poly [ADP-ribose] polymerase inhibitor; PAR = poly [ADP] ribose.)

View larger version (163K): [in this window] [in a new window]   Fig 3. Immunohistochemical staining for nitrotyrosine, an indicator of peroxynitrite formation. Widespread nitrotyrosine staining was seen in (A) vehicle-treated, (B) high-dose INO-1001-treated, and (C) low-dose cyclosporine-treated hearts. (D) There was markedly reduced nitrotyrosine formation in the combination of low-dose cyclosporine and high-dose INO-1001–treated hearts. (INO-1001 = poly [ADP-ribose] polymerase inhibitor.)

	Comment

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Calcineurin inhibitors, such as cyclosporine, are known to suppress IL-2 secretion from activated T cells, preventing further T-cell activation in a mechanism dependent upon nuclear factor of activated T cells (NFAT) activation. Their use has had dramatic effects on improving survival of recipients of heart transplants in the short-term and intermediate-term [17]. However, use of calcineurin inhibitors is associated with significant nephrotoxicity and cardiovascular side effects. There has been a focus on complementing calcineurin inhibitors with adjunctive agents seeking to inhibit alternate pathways of tissue injury, such as azathioprine or mycophenolate mofetil. The pathway leading to tissue injury and cell death via PARP overactivation is increasingly appreciated as injurious after conditions such as ischemia and reperfusion. It is plausible that addition of an agent such as INO-1001 to conventional immunosuppression may provide clinicians with the opportunity to decrease their doses of calcineurin inhibitors after transplantation. This could dramatically limit potential toxicities associated with CSA or tacrolimus in the early and late postoperative period.

As mentioned previously, peroxynitrite is formed from the combination of nitric oxide and the superoxide anion, and is a potent oxidant [5]. Peroxynitrite reacts with multiple intracellular targets, including DNA. It induces single-stranded breaks and in turn, activates PARP. PARP then catalyzes the transfer of ADP ribose moieties from NAD⁺ to nicotinamide in an attempt to maintain genomic stability. Additional ATP molecules are needed to restore the depleted NAD⁺ stores. The depletion of intracellular stores of NAD⁺ and ATP, both of which are needed for mitochondrial respiration, eventually leads to cell death via deranged cellular energetics [6]. Since peroxynitrite formation and breakdown occurs in rapid fashion, the "footprint" of peroxynitrite, nitrotyrosine, was studied in allografts. The protective effects of combination therapy on allograft survival were associated with a marked reduction in nitrotyrosine staining. Histologically, this was associated with a significant reduction in the ISHLT rejection scores. The reduction in peroxynitrite in the hearts after PARP inhibitor treatment may be related to maintenance of mitochondrial integrity and reduced superoxide release from the mitochondrial respiratory chain [18]. Alternatively, it may relate to an inhibition of mononuclear cell infiltration into the affected myocardial tissue, and, consequently, a reduction of mononuclear cell-derived reactive species formation [19]. Because cardiac transplantation is associated with the upregulation of the inducible isoform of NO synthase (iNOS), and PARP inhibition is known to suppress this effect via inhibition of nuclear factor kappa B activation [20, 21]. It is also possible that PARP inhibition, via this indirect mechanism, may downregulate the production of all reactive nitrogen species during allograft rejection.

The benefits of the heterotopic model involve the ability to transplant a mismatched heart into a physiologic environment, affording scientists an opportunity to study the evolution of a pathologic process such as ACR. Because procedures are done on rodents, multiple animals can be transplanted and interventions assessed more readily, reducing variability within groups. Crossing of MHC barriers produces a vigorous response, resulting in rejection by Day 7 on average in vehicle-treated animals. One limitation of the model is the heterotopic nature of the transplant, and as such the heart beats but is not responsible for maintaining circulatory integrity. Therefore it is likely that the Starling forces of the transplanted heart are not purely physiologic and representative of the orthotopically transplanted heart. Another drawback of the model involves the greater tendency of rodent hearts to develop graft tolerance spontaneously. We attempted to counter this issue by using subtherapeutic doses of CSA.

In summary, PARP activation after heart transplantation in rodents appears to promote tissue injury and the development of ACR. The novel, potent PARP inhibitor INO-1001 dose dependently increased allograft survival. The combination of low-dose CSA and high-dose INO-1001 conferred the greatest degree of protection to transplanted allografts. Based on the current results, we hypothesize that combination of PARP inhibitors and CSA may allow reductions in the levels of calcineurin inhibitors needed to achieve therapeutic clinical immunosuppression. This would potentially limit morbid complications associated with calcineurin inhibition.

	Notice From the American Board of Thoracic Surgery

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The 2005 Part I (written) examination will be held on Monday, December 5, 2005. It is planned that the examination will be given at multiple sites throughout the United States using an electronic format. The closing date for registration was August 1, 2005. Those wishing to be considered for examination must apply online at www.abts.org.

To be admissible to the Part II (oral) examination, a candidate must have successfully completed the Part I (written) examination.

A candidate applying for admission to the certifying examination must fulfill all the requirements of the Board in force at the time the application is received.

Please address all communications to the American Board of Thoracic Surgery, 6333 N St. Clair St, Suite 2320, Chicago, IL 60611; telephone: (312) 202-5900; fax: (312) 202-5960; e-mail: mailto:info{at}abts.org.

	Acknowledgments

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This work was funded by a grant from the National Institutes of Health (R43 HL69419) to Dr Jagtap.

	References

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1. Bennett LE, Keck BM, Hertz MI, Trulock EP, Taylor DO. Worldwide thoracic organ transplantationa report from the UNOS/ISHLT international registry for thoracic organ transplantation. Clin Transpl 2001:25-40.
2. Garrity Jr ER, Mehra MR. An update on clinical outcomes in heart and lung transplantation Transplantation 2004;77(9 Suppl):68-74.
3. Hoerbelt R, Madsen JC. Feasibility of xeno-transplantation Surg Clin North Am 2004;84:289-307.[Medline]
4. Jahania MS, Mullett TW, Sanchez JA, Narayan P, Lasley RD, Mentzer Jr RM. Acute allograft failure in thoracic organ transplantation J Card Surg 2000;15:122-128.[Medline]
5. Ferdinandy P, Schulz R. Nitric oxide, superoxide, and peroxynitrite in myocardial ischaemia-reperfusion injury and preconditioning Br J Pharmacol 2003;138:532-543.[Medline]
6. Virág L, Szabó C. The therapeutic potential of PARP inhibition Pharmacol Rev 2002;54:375-429.[Abstract/Free Full Text]
7. Fiorillo C, Ponziani V, Giannini L, et al. Beneficial effects of poly (ADP-ribose) polymerase inhibition against the reperfusion injury in heart transplantation Free Radic Res 2003;37:331-339.[Medline]
8. Southan GJ, Szabó C. Inhibitors of poly (ADP-ribose) polymerase Current Med Chem 2003;10:321-340.
9. Murakami K, Enkhbaatar P, Shimoda K, Cox RA, Burke AS, Hawkins HK, et al. Inhibition of poly (ADP-ribose) polymerase attenuates acute lung injury in an ovine model of sepsis Shock 2004;21:126-133.[Medline]
10. Farivar AS, Woolley SM, Fraga CH, et al. Intratracheal poly (ADP) ribose synthetase inhibition ameliorates lung ischemia reperfusion injury Ann Thorac Surg 2004;77:1938-1943.[Abstract/Free Full Text]
11. Khan TA, Ruel M, Bianchi C, et al. Poly (ADP-ribose) polymerase inhibition improves postischemic myocardial function after cardioplegia-cardiopulmonary bypass J Am Coll Surg 2003;197:270-277.[Medline]
12. Komjáti K, Mabley JG, Virág L, Southan GJ, Salzman AL, Szabó C. Poly (ADP-ribose) polymerase inhibition protects neurons and the white matter and regulates the translocation of apoptosis-inducing factor in stroke Int J Mol Med 2004;13:373-382.[Medline]
13. Xiao CY, Chen M, Zsengellér Z, Szabó C. Poly (ADP-ribose) polymerase contributes to the development of myocardial infarction in diabetic rats and regulates the translocation of apopotosis-inducing factor J Pharmacol Exp Ther 2004;310:498-504.[Abstract/Free Full Text]
14. Ono K, Lindsey ES. Improved technique of heart transplantation in rats J Thorac Cardiovasc Surg 1969;57:225-229.[Medline]
15. Mulligan MS, McDuffie JE, Shanley TP, et al. Role of RANTES in experimental cardiac allograft rejection Exp Mol Pathol 2000;69:167-174.[Medline]
16. Szabó G, Liaudet L, Hagl S, Szabó C. Poly (ADP-ribose) polymerase activation in the reperfused myocardium Cardiovasc Res 2004;61:471-480.[Medline]
17. Keogh A. Calcineurin inhibitors in heart transplantation J Heart Lung Transplant 2004;23(5 Suppl):S202-S206.[Medline]
18. Virág L, Salzman AL, Szabó C. Poly (ADP-ribose) synthetase activation mediates mitochondrial injury during oxidant-induced cell death J Immunol 1998;161:3753-3759.[Abstract/Free Full Text]
19. Szabó C, Lim LH, Cuzzocrea S, et al. Inhibition of poly (ADP-ribose) synthetase attenuates neutrophil recruitment and exerts anti-inflammatory effects J Exp Med 2002;186:1041-1049.
20. Szabó C, Virág L, Cuzzocrea S, et al. Protection against peroxynitrite-induced fibroblast injury and arthritis development by inhibition of poly (ADP-ribose) synthetase Proc Natl Acad Sci USA 2003;95:3867-3872.
21. Haskó G, Mabley JG, Németh ZH, Pacher P, Deitch EA, Szabó C. Poly (ADP-ribose) polymerase is a regulator of chemokine productionrelevance for the pathogenesis of shock and inflammation. Mol Medicine 2002;8:283-289.

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