The mitochondria-targeted anti-oxidant MitoQ decreases ischemia-reperfusion injury in a murine syngeneic heart transplant model.
The mitochondria-targeted anti-oxidant MitoQ decreases ischemia-reperfusion injury in a murine syngeneic heart transplant model.
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DOI：
10.1016/j.healun.2015.05.007
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发表时间：
2015-11
期刊：
影响因子：
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通讯作者：
Saeb-Parsy K
中科院分区：
文献类型：
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作者：
Dare AJ;Logan A;Prime TA;Rogatti S;Goddard M;Bolton EM;Bradley JA;Pettigrew GJ;Murphy MP;Saeb-Parsy K
心脏移植物再灌注期间自由基的产生和线粒体功能障碍是移植后缺血再灌注（IR）损伤的主要因素，IR损伤是原发性移植物功能障碍的重要潜在原因。因此，我们评估了靶向抗氧化剂MitoQ在鼠异位心脏移植模型中减少IR损伤的功效。将来自C57 BL/6供体小鼠的心脏用单独的储存溶液、含有抗氧化剂MitoQ的溶液或含有非抗氧化剂癸基三苯基鳞对照的溶液冲洗，并在移植前暴露于短（30分钟）或长（4小时）的冷保存。将移植物移植到C57 BL/6受体中，并在移植后120分钟或24小时分析线粒体活性氧产生、氧化损伤、血清肌钙蛋白、搏动评分和炎症标志物。MitoQ在冷藏期间被心脏吸收。IR前供体心脏长时间冷保存增加了IR损伤（肌钙蛋白I，搏动评分）和线粒体活性氧，线粒体DNA损伤，蛋白质羰基化，以及移植后24小时促炎细胞因子的释放。在储存溶液中向供体心脏施用MitoQ通过阻断移植物氧化损伤和抑制受体中的早期促炎反应来保护免受这种IR损伤。心脏移植后IR导致线粒体氧化损伤，冷缺血可增强线粒体氧化损伤。应进一步研究在移植前用抗氧化剂MitoQ补充供体移植物灌注，以减少IR相关的自由基产生、对IR损伤的先天免疫反应和随后的供体心脏损伤。
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. 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. 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, mitochondrial 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. 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.