Suppression of nitrosative and oxidative stress to reduce cardiac allograft vasculopathy.
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-kappaB 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.
Hasegawa
Tomomi
T
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Iwanaga
Koichiro
K
Hultquist
Donald E
DE
Liao
Hui
H
Visovatti
Scott H
SH
Pinsky
David J
DJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000009:adverse effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D015538:Nitrosation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D026361:Reactive Nitrogen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D012256:Riboflavin / Q000494:pharmacology; D014184:Transplantation, Homologous; D014652:Vascular Diseases / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*
D000975:Antioxidants; D016328:NF-kappa B; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D052247:Nitric Oxide Synthase Type II; D012256:Riboflavin