The mitochondria-targeted anti-oxidant MitoQ decreases ischemia-reperfusion injury in a murine syngeneic heart transplant model

被引:87
|
作者
Dare, Anna J. [1 ,2 ]
Logan, Angela [1 ,2 ]
Prime, Tracy A. [1 ,2 ]
Rogatti, Sebastian [1 ,2 ]
Goddard, Martin [3 ]
Bolton, Eleanor M. [2 ,4 ]
Bradley, J. Andrew [2 ,4 ]
Pettigrew, Gavin J. [2 ,4 ]
Murphy, Michael P. [1 ,2 ]
Saeb-Parsy, Kourosh [2 ,4 ]
机构
[1] Univ Cambridge, MRC, Mitochondrial Biol Unit, Cambridge, England
[2] Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England
[3] Papworth Hosp Natl Hlth Serv Fdn Trust, Cambridge, England
[4] Univ Cambridge, Dept Surg, Cambridge, England
来源
JOURNAL OF HEART AND LUNG TRANSPLANTATION | 2015年 / 34卷 / 11期
基金
英国医学研究理事会;
关键词
ischemia; reperfusion; transplantation; mitochondria-targeted anti-oxidants; MitoQ; CARDIAC COLD ISCHEMIA; TRIPHENYLPHOSPHONIUM CATIONS; PERMEABILITY TRANSITION; LUNG TRANSPLANTATION; GRAFT-SURVIVAL; REJECTION; DISEASE; PATHWAYS; CELLS; H2O2;
D O I
10.1016/j.healun.2015.05.007
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
BACKGROUND: Free radical production and mitochondrial dysfunction during cardiac graft reperfusion is a major factor in post-transplant ischemia-reperfusion (IR) injury, an important underlying cause of primary graft dysfunction. We therefore assessed the efficacy of the mitochondria-targeted anti-oxidant MitoQ in reducing IR injury in a murine heterotopic cardiac transplant model. METHODS: Hearts from C57BL/6 donor mice were flushed with storage solution alone, solution containing the anti-oxidant MitoQ, or solution containing the non anti-oxidant decyltriphenylphosphonium control and exposed to short (30 minutes) or prolonged (4 hour) cold preservation before transplantation. Grafts were transplanted into C57BL/6 recipients and analyzed for mitochondrial reactive oxygen species production, oxidative damage, serum troponin, beating Score, and inflammatory markers. 120 minutes or 24 hours post-transplant. RESULTS: MitoQ was taken up by the heart during cold storage. Prolonged cold preservation of donor hearts before IR increased IR injury (troponin I, beating score) and mitochondrial reactive oxygen species, mitochondria! DNA damage, protein carbonyls, and pro-inflammatory cytokine release 24 hours after transplant. Administration of MitoQ to the donor heart in the storage solution protected against this IR injury by blocking graft oxidative damage and dampening the early pro-inflammatory response in the recipient. CONCLUSIONS: IR after heart transplantation results in mitochondrial oxidative damage that is potentiated by cold ischemia. Supplementing donor graft perfusion with the anti-oxidant MitoQ before transplantation should be studied further to reduce IR-related free radical production, the innate immune response to IR injury, and subsequent donor cardiac injury. (C) 2015 International Society for Heart and Lung Transplantation. All rights reserved.
引用
收藏
页码:1471 / 1480
页数:10
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