中国内镜稿件信息
外泌体在心肌缺血中诊疗价值
摘要：心肌缺血疾病中，无论动脉粥样硬化、心肌梗死，还是缺血/再灌注损伤，随着临床医学的发展，除了PCI 、溶栓或优化药物治疗外，外泌体对心肌缺血的诊断治疗进入研究者的视线。在过去，外泌体被认为是细胞的废物。今天，它们被认为是真正的生物标志物和细胞间生物信息的载体。外泌体是来自胞内起源的囊泡的一个特定子集，包含不同的microrna, mrna，蛋白质和脂质。研究表明，由于生理和病理应激的不同，外泌体的含量会发生变化，最近的研究表明，在缺血性疾病中，外泌体有助于早期诊断，在细胞实验和动物模型中，外泌体有促进血管生成、抑制细胞凋亡和减少炎症等保护缺血器官的作用.本文对外泌体在心肌缺血中早期诊断与治疗的新进展进行论述。
关键词： 心肌缺血 外泌体 miRNA
Abtract：In myocardial ischemic diseases, whether atherosclerosis, myocardial infarction, or ischemic/reperfusion injury, with the development of clinical medicine, in addition to PCI, thrombolysis or optimized drug treatment, the research of exosomes on myocardial ischemia has come into researchers' sight. In the past, exosomes were considered cell waste. Today, they are considered to be the true biomarkers and vectors of biological information between cells.Exosome is a specific subset of vesicles from intracellular origin vesicles containing varies of microRNAs, mRNAs, proteins and lipids. It has been demonstrated that contents of exosomes could be altered due to different physiological and pathological stress, which could be used as clinical biomarker to reveal the disease state. In addition, according to previous studies, exosomes could exert protective roles for cardiovascular diseases such as atherosclerosis, myocardial infarction and ischemia/reperfusion injury, etc. New progress in early diagnosis and treatment of myocardial ischemia was discussed in this paper.
Keywords: myocardial ischemic exosomes, miRNA
作者简介：张秀娟（1993-），硕士研究生，硕士学位，主要从事心内科疾病治疗。Email：2550477354@qq.com
通讯作者:周立君（1960-）主任医师，教授，博士，主要从事冠心病计入治疗。Email：zhoulj0451@126.com
外泌体的生物学性质
外泌体是直径为30-120nm的双层膜性囊泡，带负电荷（-26mV），EVs可分为外泌体、微颗粒 (microvesicles) 及凋亡小体。“外泌体”一词于1981年由Trams and colleagues 首次提出，用于描述细胞系分泌的囊泡[1]。之后,这个术语是采用囊泡的直径30 - 150 nm分化期间发布[2]。此后不久，Raposo等人发现，B淋巴细胞和树突状细胞通过类似途径释放外泌体[3]。在随后的几年里，许多造血细胞和非造血细胞来源的其他细胞类型，如细胞毒性T细胞、血小板、肥大细胞、神经元、少突胶质细胞和肠上皮细胞，已经被证明释放外泌体[3，4]。此外,外泌体也被发现存在于液体环境中，包括血液[5],精液[6],尿[7],唾液[8]等。
所有外泌体都含有参与膜转运和融合的蛋白(GTPases, annexins, flotillin)、四聚体蛋白(CD9, CD63, CD81, CD82)、热休克蛋白(Hsc70, Hsp90)、参与多泡体生物发生的蛋白(Alix, TSG101)、脂相关蛋白和磷脂酶【9,10】。通过质谱分析，已经鉴定出4500多种不同的蛋白质与外泌体有关，可能是作为细胞间通讯的载体【11】。除蛋白质外，外泌体还富集于某些与raft相关的脂质，如胆固醇(主要是B淋巴细胞)、神经酰胺(涉及外泌体与溶酶体的分化)、其他鞘脂质，以及长而饱和脂肪酸酰基链的磷酸甘油脂【12,13,14】.已经证明外泌体也含有RNA，特别是miRNA(100多个序列)和mRNA(1300多个序列)，其中一些可以被靶细胞翻译成蛋白质【15,16】。
外泌体作为生物标志物
心肌梗死(MI)时，心脏释放不同的酶、生长因子和细胞因子，可作为心脏损伤的标志物。心肌肌钙蛋白(cTn)和肌酸激酶MB (CK-MB)是心肌梗死最常用的生物标志物【17,18】。由于这些生物标志物相对较晚出现，10 - 15%的MI患者在入院时血液检测呈阴性【19,20】。迟发性心肌梗死的确认会导致发病率和死亡率的增加。目前仍需要对MI[21]进行新的早期生物标记。
越来越多的证据表明循环的microRNAs (miRNA)可能是潜在的生物标志物候选，因为它们在应激时的血液中会高度特异性的升高，包括MI[22,23]。对于疑似急性冠脉综合征(ACS)患者[3],我们发现许多microrna(例如miRNA-1,-21,-146,-21,-499)增加，这对预测心肌梗死有良好的诊断价值。然而,关于循环中这些microrna的释放时间、潜在来源和运输缺乏数据考证。EV是被研究最多的细胞外miRNA转运实体。临床数据显示，肌特异性mirna在心肌梗死3小时内升高，并在心肌梗死后3 - 5天内恢复正常[24,26,27]。有趣的是，在小动物模型中，在1小时后已经可以观察到最初的增加[25,28]。重要的是，Jansen等人[29]证实，miRNA-126和miRNA-199a仅在EV中测量时才能预测心血管事件。
在CVD中，观察到EV的增加，并且它们的含量随疾病的严重程度[24]而改变。在这里，我们证明了EV是在心脏I/R损伤时释放的。此外，在猪心肌梗死模型中连续的血浆收集表明，在损伤后EV和循环mirna均显著增加。缺血开始2.5 h后，血浆中心脏和肌肉特异性的mirna迅速增加，而1 h后，EV已经增加【30】。
外泌体在动物模型及细胞中的研究
RIC（Investigation of remote ischemic conditioning ）的研究发现，心肌梗死后4周内经RIC治疗的大鼠与未治疗的大鼠相比，射血分数更好，LV重塑程度更轻[64]。从RIC治疗后的大鼠血清中分离出的外泌体增加了组织纤维化负调节因子miR-29a的水平;经RIC治疗后，梗死边缘区域的miR29a表达水平也显著升高[31]远端肢体缺血预适应 (remote ischemic preconditio-ning, RIPC）是目前缺血性心脏病的研究热点【32】 RIPC具有减轻冠状动脉支架置入术引起的再灌注损伤，改善冠心病患者预后的作用【33】。有研究发现，RIPC后远端缺血区释放大量得外泌体入血，携带高浓度的miR-24的外泌体随血液循环至再灌注心脏内，被IRI心肌细胞摄取吸收，miR-24再心肌细胞内下调靶蛋白Bim的表达，减轻心肌细胞凋亡，减少缺血再灌注损伤【34】。有实验证明，在用双氧水诱导的凋亡的大鼠心肌细胞模型中发现，经外泌体处理的心肌细胞与对照组对比，凋亡细胞占总细胞的百分比明显下降，存活细胞增加，同时，伴有BCL-2表达增加，BAX蛋白表达下降【35】。Gallet R 等研究证实心脏球衍生的细胞外泌体可减少疤痕，阻止心室重塑，改善在猪AMI和CMI中的LVEF。定量分析发现，胶原蛋白含量不仅在梗死区，而且在边界和偏远地区都有所下降。这一发现表明，外泌体治疗不仅可以减少注射部位的纤维化，而且还具有更广泛的抗纤维化作用。这些外泌体介导细胞间的通讯，至少部分通过转移独特的microRNAs (miRNAs)和其他非编码的RNAs(特定于某细胞类型)，通过减少凋亡或减少炎性细胞浸润发挥作用【36】。Luo Q等进行动物体外实验结果显示，在缺氧诱导过程中，mir -126-过度表达脂肪干细胞（ADSCs）的外泌体通过降低炎症因子表达而降低H9c2心肌细胞损伤。同时，也降低了H9c2细胞的纤维蛋白相关蛋白的表达。另外，mir - 126显著促进微血管生成和迁移【37】.Etsu Suzuki等研究证明间充质干细胞（mesenchymal stem cells (MSCs),通过分泌旁分泌因子改善心脏功能，而不是通过MSCs直接分化为心肌细胞类型【38】。Lai等发现，人类胚胎干细胞(ESC)的上清液中含有与外泌体相对应的小颗粒(直径50-100纳米)。当采用小鼠心肌缺血/再灌注损伤模型时，这些外泌体显著降低梗死面积。此外，他们发现ATP和烟酰胺腺嘌呤二核苷酸的组织水平显著升高，而活性氧的组织水平在体外培养后显著降低【39】。Feng等证明了在缺血预处理后小鼠中，MSCs分泌的外泌体含有大量的miR-22。当给予AMI小鼠时，这些mir -22通过对甲基- cpg结合蛋白2的下调，对心肌细胞产生抗凋亡作用【40】.Yu等发现msc_gata -4通过下调磷酸酶和tensin homolog (PTEN)，激活抗凋亡Akt和细胞外信号调节激酶而发挥作用【41】。Barile L等证明，与骨髓源间充质干细胞(bone marrow-derived mesenchymal stem/progenitor cells BMCs)分泌的外泌体相比，心源祖细胞（cardiac-resident progenitor cells CPCs）分泌的外泌体可以更有效地防止星孢菌素（staurosporine）诱导的心肌细胞凋亡。在大鼠永久冠状动脉闭塞后，CPCs分泌的外泌体比BMCs分泌的外泌体更有效地减少瘢痕大小和改善心室功能。两种外泌体都可以刺激血管形成。而前者，在缺血/再灌注后可增强心室功能。妊娠相关的血浆蛋白a (PAPP-A)，这是CPCs与BMCs外泌体中最丰富的蛋白之一。在CPCs外泌体表面检测到PAPP-a的活性形式。这些囊泡通过IGF结合蛋白-4 (IGFBP-4)的蛋白溶解裂解释放胰岛素样生长因子-1 (IGF-1)，导致IGF-1受体激活，胞内Akt和ERK1/2磷酸化，caspase活化减少，心肌细胞凋亡减少。PAPP-A基因在体外和体内都阻止了共体介导的心肌保护。这些结果表明，CPCs分泌的外泌体可能比BMCs分泌的外泌体更具有心脏保护作用，而PAPP - A介导的IGF-1释放可能解释了这一好处。它们阐明了一种普通机制，即外泌体可以通过其表面活性蛋白酶作用，从而释放出配体与配体结合的跨膜受体【42】. Ting-Yu chang 等发现在CAD患者中有12个miRNA表达，并且相较正常人群高表达。在CAD (endothelial colony-forming cells ECFCs)中，miR-146a-5p或miR-146b-5p的下调增强了病变ECFCs的迁移和管内形成活动。相反，在健康的ECFC中，miR-146a-5p或miR-146b-5p的过表达抑制了ECFCs的迁移和成管。miR-146a-5p或miR-146b-5p的下调可以在CAD ECFCs中恢复CAV1和RHOJ水平。外周血EPCs数量与血管生成相关表型及冠心病的严重程度呈负相关。研究揭示了miR-146a-5p和miR-146b-5p是一种新的潜在的血管生成调控miRNAs，它们被CAD ECFCs上调并可能分泌。在这里，我们提供了间接证据表明，循环的miR-146a-5p和miR-146b-5p，包括游离的和外体相关的形式，可能被HLTY ECFCs吸收，导致病变ECFCs的扩增，这就为CAD治疗提供新的策略【43】。研究发现miR-22通过靶向Mecp2至少部分地保护缺血心肌【44】，而此前有报道称Mecp2在缺血心脏【45】中上调。与miR-22 mimic或Mecp2处理相比，用ExoIPC处理梗死心脏的心脏预后更好。从骨髓间充质干细胞中释放出来的外泌体作为携带miR-22到缺血性心肌细胞的载体，使我们能够指定外源性骨髓间充质干细胞在心肌梗死后心脏恢复中的作用。Hao Li等实验证明，在isc-Exo中，miR-939-5p明显下调。通过抑制和过表达分析，我们发现miR-939-5p通过靶向iNOS调控血管生成。miR-939-5p抑制iNOS的表达和活性，降低内皮NO的生成，最终损害血管生成。所以，来自心肌缺血患者的外泌体通过miR-939-iNOS-NO通路促进血管生成【46】。GATA-4在心脏的早期发育中起着重要的作用，其表达的增加促进了前体细胞向心肌细胞的分化.BMSCs中GATA-4的表达导致其产生了通过外泌体转移到缺氧心肌细胞的抗凋亡mirna，导致Akt和ERK通路的激活【47】。mir - 146 a是一个GATA-4-responsive抗凋亡microrna,负调节TLR-mediated NF-κB通路,减少炎症因子。含mir -146a的外泌体在心肌梗死开始时(即心肌梗死开始时)注入心肌梗死后增加了LVEF【48】【49】。Helia Namaz等认为心源性细胞(CDCs)已成为心脏保护和修复最有前途的干细胞类型之一。外泌体对于人类CDCs的再生作用是必需的，并且模拟了CDCs对心脏的保护作用。在正常氧(18% O2)和缺氧(1% O2)条件下培养CDCs，通过微分离心分离条件培养基中分离得到CDC-exosomes，证明cdc分泌的外泌体具有预防心肌细胞凋亡的潜力，有望为缺血性心脏病提供一种有前途的治疗策略【50】。Xiao C等发现，在轻度缺血胁迫下，自噬可以通过降解受损的细胞器以产生ATP，从而保持细胞活力，但在严重缺血条件下，自噬可促进细胞死亡，使心脏功能恶化。骨髓间充质干细胞移植在心肌梗死后的有益作用至少部分是由于通过主要含有miR-125b-5p的排泄外泌体改善了自噬通量【36】。Li F等发现循环miR-29a水平升高与人心功能受损密切相关，包括射血分数和NT-proBNP水平。肥胖人群血浆介导的心肌细胞外泌体线粒体无活性，但使用miR-29a海绵预处理可减弱外泌体miR-29a诱导的ATP生成减少、基础耗氧量和线粒体复合物I活性。在小鼠体内研究中，高脂肪饮食损害心脏功能、正常结构和线粒体活动，而miR-29a海绵改善心脏状况。研究揭示了循环miR-29a与人体心脏参数的相关性，为miR-29a海绵治疗肥胖介导的心功能障碍提供了有力证据【37】。
以上研究表明，外泌体为心肌缺血治疗提供新方向，但有关外泌体在心肌缺血治疗中潜在的具体机制还需进一步探索。其重点是外泌体中所携带的蛋白，miRNA及脂质，如何作用于靶点发挥作用，面临重大挑战，克服这一难题将为心血管疾病诊断及治疗开拓新领域。
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