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

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• 作者：Anna J. Dare ; MBBCh ; PhD^a ; Angela Logan ; PhD^a ; Tracy A. Prime ; BSc^a ; Sebastian Rogatti ; BSc^a ; Martin Goddard ; MBBCh ; FRCPath^b ; Eleanor M. Bolton ; PhD^c ; J. Andrew Bradley ; MBBCh ; PhD ; FRCS^c ; Gavin J. Pettigrew ; MBBCh ; MD ; FRCS^c ; Michael P. Murphy ; PhD^a ; ^{mpm@mrc-mbu.cam.ac.uk" class="auth_mail" title="E-mail the corresponding author} ; Kourosh Saeb-Parsy ; MBBCh ; PhD ; FRCS^c
• 关键词：ischemia ; reperfusion ; transplantation ; mitochondria-targeted anti-oxidants ; MitoQ
• 刊名：Journal of Heart and Lung Transplantation
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：34
• 期：11
• 页码：1471-1480
• 全文大小：777 K

文摘

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, 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.

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.