MG53 protein protects against multiorgan ischemia/reperfusion injury: present and future

doi:10.3969/j.issn.2095-4344.2017.20.021

Abstract

Abstract:

BACKGROUND: In recent years, with the progress of shock therapy as well as the establishment and promoted application of arterial bypass grafting, thrombolytic therapy, percutaneous transluminal coronary angioplasty, extracorporeal circulation on cardiac surgery, cardiopulmonary resuscitation, limb replantation, and organ transplantation, blood reperfusion in multiple organs after ischemia has been achieved. However, the organs which undergo a period of ischemia appear to have the performance of damage aggravation.
OBJECTIVE: To summarize the research progress of MG53 protein in protecting five organs from ischemia/reperfusion injury, thereby providing reference for further in-depth study.
METHODS: A computer-based online search of PubMed, Duxiu Knowledge Search and CNKI databases was performed for relevant literatures puldished between 1986 and 2016. The key words were “MG53, TRIM, Mitsugumin53, ischemic, reperfusion, preconditioning, postconditioning, RISK, membrane damage, Connexin43, KChIP2” in English and “MG53, ischemia/reperfusion” in Chinese. Finally 61 eligible articles were reviewed in accordance with the inclusion and exclusion criteria.
RESULTS AND CONCLUSION: As a muscle-specific TRIM family protein, endogenous MG53 is involved in the repair of muscle cytomembrane damage, and the protective effects of ischemic preconditioning and postconditioning. Exogenous recombinant human MG 53 protein not only repairs membrane damage of various muscles and non-muscle cells, but also protects the myocardium, skeletal muscle, brain, lung and kidney from ischemia/reperfusion injury.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Muscles, Blood Vessels, Ischemia, Organ Transplantation, Tissue Engineering

CLC Number:

R318

Liu Teng-fei, Zhou Jian-kang, Huang Tuan-jie, Xing Qu, Cheng Kang, Li Peng, Li Dong-peng, Yang Bo, Ma Shan-shan, Guan Fang-xia . MG53 protein protects against multiorgan ischemia/reperfusion injury: present and future[J]. Chinese Journal of Tissue Engineering Research, 2017, 21(20): 3248-3254.

Figures/Tables 3

2.2.1 MG53蛋白对心肌缺血再灌注损伤的保护作用冠心病是严重危害人类健康的心血管疾病，冠状动脉血管的动脉粥样硬化病变会使血管腔变得狭窄或堵塞，从而导致心肌缺血，心肌缺血又会导致心肌梗死。对缺血心肌适时的再灌注是保持心肌细胞活力的惟一方法；但再灌注又会引起心律失常等一些更为严重的损害。研究发现MG53蛋白在心肌缺血再灌注损伤中起到保护作用[19-21]；但心肌缺血再灌注损伤本身又会降低内源性MG53蛋白的表达[19]。研究发现，在心肌组织中，MG53蛋白存在两种内生机制，即缺血预适应和缺血后适应。对心肌缺血再灌注损伤来说缺血预适应和缺血后适应是两种非常强大的内源性保护机制。Cao[19]和Zhang 等[21]通过动物实验分别证实了缺血预适应和缺血后适应对心肌缺血再灌注损伤的保护作用。另外，当内源性MG53蛋白不能满足心肌缺血再灌注损伤的需要时，给予重组人MG53蛋白就成为了一种新的治疗方式[2]。在心肌缺血再灌注损伤模型中无论缺血前还是缺血后给予重组人MG53蛋白均可起到保护心肌细胞，改善心功能的作用[22-23]。 2.2.2 MG53蛋白对骨骼肌缺血再灌注损伤的保护作用机体大负荷运动会引起骨骼肌的剧烈收缩，肌肉收缩压迫血管，长时间运动导致血管对骨骼肌的供血不足，骨骼肌出现缺血缺氧的情况。运动后休息期间骨骼肌的供血逐渐恢复正常，缺血缺氧得到缓解。该过程类似于临床上的缺血再灌注过程，这种缺血再灌注也会引起骨骼肌损伤，即骨骼肌缺血再灌注损伤。Lorenz等[24]证实了缺血预适应对骨骼肌再次受到缺血再灌注损伤具有保护作用，但是当骨骼肌缺血时间超过5 h后，缺血预适应的保护作用失效。研究发现，在小鼠骨骼肌缺血再灌注损伤模型中，MG53蛋白基因敲除小鼠更易受到损伤，而野生型小鼠相对不容易受到损伤，证明了MG53蛋白对受损肌肉组织发挥着重要的保护作用[25]。这些研究提示了MG53蛋白可能是治疗骨骼肌缺血再灌注损伤的一个新思路。 2.2.3 MG53蛋白对脑缺血再灌注损伤的保护作用脑血管病是世界上发病率、死亡率和致残率很高的疾病之一。国内脑血管病中约70%为缺血性脑血管病，主要是由大脑动脉尤其大脑中动脉闭塞引起[26]。脑缺血后梗死组织周边存在的缺血半暗带恢复再通是缺血性脑血管疾病治疗的基础。但缺血区恢复再灌注后会加重脑组织和细胞损伤，即脑缺血再灌注损伤。实验证明，大脑组织并不表达MG53蛋白[22]。Moloughney等[27]发现重组MG53蛋白可以提高神经细胞的膜修复能力，发挥神经保护作用。由此，研究者采用大鼠脑缺血再灌注损伤模型，观察无MG53蛋白表达的器官是否能够在重组人MG53蛋白的治疗下得到改善。研究发现，MG53蛋白能透过血脑屏障[28]；在术前30 min及术后 0，1，2，4 h分别给予重组人MG53蛋白，均能使神经系统症状得到改善，降低神经系统Zea-Longa评分，减轻脑梗死面积以及坏死程度，且重组人MG53蛋白的保护作用呈时间相关性，有效时间窗为4 h。这一研究为临床治疗缺血性脑血管病提供了新的方法[29]。 2.2.4 MG53蛋白对肺脏缺血再灌注损伤的保护作用在临床上心肺移植手术、心脏动脉搭桥术、心肺脑复苏以及休克等均会导致肺缺血再灌注损伤。肺缺血再灌注损伤已成为肺移植术后重要的死因之一[30-31]。在肺缺血再灌注损伤模型中，重组人MG53蛋白能降低肺脏湿干比例以及炎性介质的浸润，提高小鼠的生存率[1，32]。给予急性肺损伤的实验动物静脉注射或吸入重组人MG53蛋白，可有效减轻肺损伤的症状，重复使用重组人MG53蛋白可改善慢性损伤对肺部结构的改变[32]。另外在肺脏缺血再灌注损伤前提前给予大鼠下肢远程缺血预适应，可以使肺脏中的MG53蛋白表达量显著增加，这提示骨骼肌合成、释放的MG53蛋白在下肢远程缺血预适应处理后参与了对肺脏缺血再灌注损伤的保护作用[33]。 2.2.5 MG53蛋白对肾脏缺血再灌注损伤的保护作用肾脏缺血再灌注损伤是一种常见的临床病理生理过程，多见于严重烧伤、低血容量性休克、肾动脉阻断以及肾脏移植等情况，可以造成肾衰竭或肾功能障碍。近年来发现，重组人MG53蛋白对肾脏缺血再灌注损伤具有保护作用[1，34]。肾脏为高灌注器官，对缺血缺氧较敏感。例如在严重烧伤后，尤其是大面积烧伤后，机体体液快速丢失，导致急性的肾缺血缺氧。肾脏随之会发生一系列显著的形态改变，而这些形态改变就与肾功能障碍的发生、发展密切相关。另外在小鼠30%Ⅲ度烫伤模型中，给予重组人MG53蛋白静脉注射，观察其对烧伤引起的肾脏缺血再灌注损伤的保护作用。研究发现重组人MG53蛋白治疗组的小鼠生存率高于对照组，并且观察到治疗组肾小管空泡的变性和坏死程度均比对照组有明显的减轻[35]。 2.3 MG53蛋白对器官缺血再灌注损伤的保护机制在MG53蛋白对器官缺血再灌注损伤的保护机制研究中，心肌缺血再灌注损伤也是一个主要的研究对象。研究发现，心肌缺血预适应和缺血后适应或MG53蛋白均能激活RISK信号通路[19，21]。研究发现，心肌缺血预适应和缺血后适应虽然也能激活生存活化因子增强(survivor activating factor enhancement，SAFE)信号通路，但并不能通过MG53蛋白来触发STAT磷酸化，所以说MG53蛋白不参与SAFE信号通路[36-37]。另外，MG53蛋白介导的膜修复过程也是MG53蛋白对器官缺血再灌注损伤起保护作用的一个重要机制。除此之外，MG53蛋白对器官缺血再灌注损伤的保护机制还可能有：MG53蛋白抑制Cx43蛋白的去磷酸化和重分布、MG53蛋白上调KChIP2蛋白的表达等。总之，MG53蛋白对器官缺血再灌注损伤的保护机制研究仍需要进一步的深入。 2.3.1 RISK信号通路缺血预适应和缺血后适应在心肌中可内生出大量的MG53蛋白，而MG53蛋白参与缺血预适应和缺血后适应的心肌保护作用是通过激活RISK信号通路实现的[19，21]。RISK信号通路主要包括PI3K-Akt-糖原合酶激酶3β(PI3K-Akt-glycogen synthase kinase-3β，PI3K-Akt-GSK3β)和细胞外信号调节激酶1/2(extracellular signal-regulated kinase 1/2，ERK1/2)信号通路。Cao等[19]证明了MG53蛋白参与缺血预适应的心肌保护与PI3K、Akt、GSK和ERK1/2磷酸化水平有关，最终证实MG53蛋白在RISK信号通路上发挥着至关重要的作用。研究还发现MG53蛋白与微囊蛋白3形成复合物后再与PI3K的P85亚基结合从而激活RISK信号通路[19]。MG53蛋白的N端和C端能分别与微囊蛋白3和p85亚基结合[21]。PI3K-Akt-GSK3β信号通路的激活会引起Akt磷酸化水平的升高，而PI3K-Akt-GSK3β信号通路的终末效应器是GSK3β，最终实现GSK3β的磷酸化。另外MG53蛋白也能提高ERK1/2的磷酸化水平，已证实激活ERK1/2信号通路同样可使其下游的GSK-3β发生磷酸化[38]。在这里值得一提的是，缺血再灌注损伤的一个重要途径就是开放线粒体通透性转换通道通透性的增高，导致开放线粒体通透性转换通道的开放，从而促进促凋亡蛋白从线粒体中释放到细胞浆中，引起细胞凋亡或坏死[39-40]。进一步研究发现，GSK3β被RISK信号通路磷酸化修饰之后失去了开放线粒体通透性转换通道的作用，从而减少了线粒体膜电位崩解和线粒体途径的细胞凋亡，发挥心肌保护作用[41]。 2.3.2 MG53蛋白介导的膜修复机制器官缺血再灌注损伤通常伴随着细胞膜损伤的发生。内源性MG53蛋白作为一种肌特异性膜修复蛋白，能修复心肌和骨骼肌损伤的细胞膜。在MG53蛋白介导的膜修复过程中，存在着多种膜修复因子如微囊蛋白3、Dysferlin和转录释放因子等，其中微囊蛋白3是一个调节因子，能够稳定由MG53蛋白介导的膜修复过程；Dysferlin能促进膜修复过程中囊泡的融合；转录释放因子是一个停靠蛋白，在损伤部位，绑定MG53蛋白寡聚体于暴露的膜胆固醇上。研究表明，暴露的膜胆固醇是MG53蛋白介导的膜修复的始发因子[20]。外界氧化物的流入细胞内后，MG53蛋白被氧化并在卷曲螺旋结构域亮氨酸拉链的帮助下促成MG53蛋白的寡聚化，起到了稳定MG53蛋白修复的作用[22，42]。MG53蛋白寡聚体与细胞内囊泡关联，招募其他膜修复因子如微囊蛋白3和Dysferlin等，从而形成一个修复复合体[43-45]。同时MG53蛋白通过识别囊泡和质膜上的磷脂酰丝氨酸并在驱动蛋白和肌球蛋白的帮助下将膜修复复合体转运至膜损伤部位[22，46-47]。然后转录释放因子作为中介，绑定MG53蛋白寡聚体于细胞内囊泡和质膜内部的胆固醇上。最后在Ca2+依赖的Dysferlin的作用下，使囊泡与质膜发生融合，完成修复过程[48-49]，见图2。"

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