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This Article Full Text Full Text (PDF) All Versions of this Article: 296/4/H1007    most recent 00498.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hasegawa, T. Articles by Pinsky, D. J. Search for Related Content PubMed PubMed Citation Articles by Hasegawa, T. Articles by Pinsky, D. J.

Suppression of nitrosative and oxidative stress to reduce cardiac allograft vasculopathy

¹Departments of Internal Medicine and ²Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; and ³Department of Chemistry and Biochemistry, Oberlin College, Oberlin, Ohio

Submitted 12 May 2008 ; accepted in final form 16 January 2009

Oxidant injury occurs when an organ is severed from its native blood supply and then reperfused and continues during subsequent periods of immune attack. Experiments here test the hypothesis that an antioxidant given only in the peri-reperfusion period protects against not only oxidative but also nitrosative stress, leading to reduced vasculopathy long after cardiac allotransplantation. Experiments were performed using a murine heterotopic cardiac transplantation model. An antioxidant, in the form of intraperitoneal high-dose riboflavin, was given to recipients during the initial 3 days after transplantation. Antioxidant-treated mice showed significantly longer graft survival than control mice. At 4 h after transplantation, antioxidant treatment significantly reduced graft lipid peroxidation and oxidized DNA and preserved antioxidant enzyme activity. At day 6 posttransplantation, the redox-sensitive transcription factor nuclear factor-B and inducible nitric oxide synthase were significantly reduced following antioxidant treatment, with concomitant reduction of nitrotyrosine. Despite the limited duration of antioxidant treatment, both acute and chronic rejection were significantly suppressed. In vitro experiments confirmed suppression of nitrosative and oxidative stress and cardiomyocyte damage in antioxidant-treated cardiac allografts. Collectively, antioxidant administration during the initial 3 days after transplantation significantly reduces nitrosative and oxidative stress in cardiac allografts, modulates immune responses, and protects against vasculopathy.

antioxidant; ischemia-reperfusion injury; inducible nitric oxide synthase; nuclear factor-B; riboflavin