Alexander S. Farivar, MD, Anton S. McCourtie, MRCS, Brendan C

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Poly (ADP) Ribose Polymerase Inhibition Improves Rat Cardiac Allograft Survival Alexander S. Farivar, MD, Anton S. McCourtie, MRCS, Brendan C. MacKinnon-Patterson, BS, Steven M. Woolley, MRCS, Andrew D. Barnes, PharmD, Min Chen, MD, PhD, Prakash Jagtap, PhD, Csaba Szabó, MD, PhD, Christopher T. Salerno, MD, PhD, Michael S. Mulligan, MD The Annals of Thoracic Surgery Volume 80, Issue 3, Pages 950-956 (September 2005) DOI: 10.1016/j.athoracsur.2005.02.035 Copyright © 2005 The Society of Thoracic Surgeons Terms and Conditions

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.) The Annals of Thoracic Surgery 2005 80, 950-956DOI: (10.1016/j.athoracsur.2005.02.035) Copyright © 2005 The Society of Thoracic Surgeons Terms and Conditions

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.) The Annals of Thoracic Surgery 2005 80, 950-956DOI: (10.1016/j.athoracsur.2005.02.035) Copyright © 2005 The Society of Thoracic Surgeons Terms and Conditions

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.) The Annals of Thoracic Surgery 2005 80, 950-956DOI: (10.1016/j.athoracsur.2005.02.035) Copyright © 2005 The Society of Thoracic Surgeons Terms and Conditions