MicroRNA在心肌梗死临床诊疗中的应用进展

王 梓， 吕迁洲， 李晓烨

复旦大学附属中山医院药剂科，上海 200032

·综述·

MicroRNA在心肌梗死临床诊疗中的应用进展

王 梓， 吕迁洲， 李晓烨*

复旦大学附属中山医院药剂科，上海 200032

微小RNA(micro-ribonucleic acid, microRNA/miRNA)是一种小的非编码RNA，在调控基因的转录过程中起着重要作用。近年来研究发现，miRNA参与心肌细胞发育、增殖、凋亡等进程，可作为一种新型的生物标志物，在急性心肌梗死的早期诊断、预后甚至治疗等方面扮演重要角色。然而，目前miRNA在检测技术、机制研究及临床试验方面仍面临诸多问题和挑战。本文就上述系列内容作一综述。

microRNA；急性心肌梗死；心血管疾病；生物标志物

微小RNA(micro-ribonucleic acid, microRNA/miRNA)是一种包含约20～23个核苷酸的短链非编码RNA，在调控基因转录的过程中扮演着重要角色。1993年，Victor Ambros和Gary Ruvkin实验室最早在线虫中证实了miRNA的存在[1]。miRNA通常由细胞外转运体(如脂蛋白等)转运，也可以微泡或微囊的形式包裹起来，因此miRNA能够稳定地存在于血液循环中。据估计，人类基因组编码了1 000多种miRNA，这些miRNA调控着约1/3的基因[2]。近年来研究[3]发现，这些miRNA调控着许多细胞进程，如细胞增殖、分化、发育和凋亡。同时，在临床上，miRNA不仅在肿瘤中扮演生物标志物的角色，也能发挥对心血管疾病的诊疗作用[4-5]。

1 miRNA作为心肌梗死诊断及预后的生物标志物

急性心肌梗死(acute myocardial infarction, AMI)是死亡率最高的心血管疾病之一，明确的早期诊断在AMI的治疗中至关重要。长期以来，心肌肌钙蛋白T(cardiac troponin T, cTnT)或高敏心肌肌钙蛋白T(high-sensitivity cardiac troponin, hs-cTnT)是诊断AMI的金标准[6]。然而，cTnT或hs-cTnT的特异性较低，一些其他疾病(如高血压危象、肾衰、心衰等)也会引起cTnT升高，容易误诊。另外，cTnT或hs-cTnT的升高往往出现在AMI发生后3～6 h，可能延误诊断[7]。因此，寻找更加敏感、更加特异的生物标志物，尽早诊断AMI，能够降低患者死亡率。近年来的研究[8-9]显示，一些miRNA在AMI中会发生改变，提示其可作为新型的生物标志物。

1.1 miRNA在心肌梗死早期诊断中的价值 研究[10-11]表明，多种miRNA水平在心肌梗死早期阶段出现明显变化，其中4种心源性和肌源性的miRNA研究最为广泛：miRNA-1(miR-1)、miRNA-133(miR-133)、miRNA-208(miR-208)、miRNA-499(miR-499)。

miR-1主要在心肌及骨骼肌中表达，包括2种亚型，miR-1-1和miR-1-2，分别由染色体18和染色体20的不同基因编码。miR-1通过抑制间隙连接蛋白(gap junction alpha-1 protein, GJA 1)和钾内向整流通道超家族J成员2(potassium inwardly rectifying channel subfamily J member 2, KCNJ 2)调节心肌再生和分化[12]。在心肌细胞坏死模型中，miR-1可以稳定地维持至少24 h。而在大鼠AMI模型中，miR-1迅速释放入血，并在AMI后6 h达到峰值[13]。在一项包含56例AMI患者和28例非AMI患者的研究中，AMI患者血浆中miR-1明显增高，并且在第14天回到基线[14]。另外，Ai等[15]在对159例患者的研究中发现，AMI组患者血浆中miR-1水平显著高于非AMI组，且该指标与年龄、性别、血压等无关，与QRS波相关。同时，在非AMI患者和AMI患者血浆中，miR-1的受试者工作特征曲线(receiver operating characteristic curve, ROC)下面积(area under curve，AUC)为0.774 0。这提示在临床上可以将miR-1作为一种独立的生物标志物，通过检测血浆中的miR-1含量，能及早并且较准确地提示AMI，有助于对AMI患者进行早期治疗。

miR-133在心肌、骨骼肌及平滑肌中都有表达，包括miR-133a和miR-133b 两种，其中miR-133a与miR-1处于相同的染色体位点，并对平滑肌细胞的调节起着关键作用[16]。在对斑马鱼的研究中，Yin等[17]发现，miR-133可能通过作用于靶点GJA 1进而抑制心肌增殖。在小鼠的AMI模型中，血浆中的miR-133水平明显增高并且在6 h即达到峰值[11]。在1项包含了13例AMI患者、176例心绞痛患者及127例对照组中，AMI患者血浆中的miR-133a呈时间依赖性地增加到72.1倍。同时，研究发现miR-133a在冠脉狭窄程度不同的患者中含量存在显著差别，提示临床上可以通过测量miR-133a水平来预测冠脉阻塞的严重性[18]。Peng等[19]研究了186例患者，其中包括76例AMI患者，也发现患者血浆中的miR-133与AMI的发生相关，并指出其可能改善AMI预测风险的分层效果。由于miR-1和miR-133a在心肌和骨骼肌中均高表达，因此相比于miR-208，这2种miRNA在诊断心肌损伤的特异性方面具有一定局限性。因此，在利用miR-1和miR-133a诊断AMI时，应排除骨骼肌损伤[20]。

miR-208主要在心肌中表达，由α肌球蛋白重链(myosin heavy light, MYH)编码。miR-208包括miR-208a和miR-208b，分别由MYH6和MYH7编码[21]。miR-208a在心肌梗死模型的组织和血清中的高表达可能是由cAMP/PKA信号通路介导的[22]。在小鼠AMI模型中，miR-208a在心梗后4 h和24 h分别升高36倍和51倍[23]。同时，AMI患者血浆中的miR-208水平也比正常人明显升高[24]。除此之外，Han等[25]还发现在发生2～3处血管狭窄的AMI患者中，血浆miR-208水平明显高于仅发生1处血管狭窄的患者。另外，AMI患者在PCI术后，miR-208水平也会明显降低。Wang等[10]研究发现，非AMI患者血浆中几乎测不到miR-208a，但在90.9%的AMI患者中都能检测到该指标。同时，用miR-208a诊断AMI时，AUC为0.965，而传统标志物cTnI的AUC为0.987，说明miR-208a能够准确地诊断AMI。这些研究都表明血浆中miR-208与心肌梗死程度密切相关，可能作为新型的AMI生物标志物。

miR-499也是一种心肌特异性的miRNA，由MYH7B基因编码[26]。在大鼠心梗模型中，血浆中miR-499水平显著升高。同时，AMI患者出现胸痛症状12 h后，miR-499可达到峰值，相比于miR-1和miR-133较延缓[11]。在一项包含142例AMI患者、85例非AMI的胸痛患者以及100例健康者的研究中，AMI患者血浆中miR-499也明显升高[27]。有研究[28]表明，在老年非ST段升高心肌梗死(non-ST-elevation myocardial infarction, NSTEMI)患者中，hs-cTnT的AUC为0.70，而miR-499-5p的AUC为0.86。这说明血液中升高的miR-499-5p比hs-cTnT能够更准确地预测患者1年内的死亡风险。

除了miR-1、miR-133、miR-208和miR-499之外，研究显示其他的miRNA也可作为心肌梗死的生物标志物：如miR-19[29]、miR-122-5p[30]、miR-19b-3p[1]、miR-134-5p[1]、miR186-5p[1]、miR-221-3p[31]、miR-30d-5p[32]、miR-125b-5p[32]、miR-486[33]、miR-150[33]、miR-10a[34]、miR-328[35]、miR-134[35]、miR-22-5p[36]、miR-93-5p[37]、miR-145[38]等。同时，研究也表明，联合2种或多种miRNA能够增加AUC值，可能会有助于提高诊断敏感性和特异性[39-40]。随着基因芯片技术的发展及miRNA含量检测技术的优化，miRNA作为心肌梗死生物标志物的前景值得期待。

1.2 microRNA在心肌梗死预后中的价值 miRNA除了在AMI的早期诊断方面具有一定价值外，在AMI的预后预测上也能发挥作用。在一项对359例AMI患者的6个月随访中发现，心室重构患者血浆中miR-208b和miR-34a水平明显升高[41]。另外，Dong等[42]证实，miR-145是一种独立的心血管事件预测因子，能够作为心肌梗死长期预后的生物标志物。另外一项研究[43]中，研究人员对424例心肌梗死的患者进行30 d随访，同时，用左心室射血分数(left ventricular ejection fraction, LVEF)评估左心室收缩功能。结果显示血浆中增加的miR-208b和miR-499与增加的死亡风险和心衰风险密切相关。然而，一些研究者也对miRNA与AMI预后的相关性表示质疑。Gidlöf等[43]和Widera等[44]认为，将这些miRNA作为预后指标仍有待商榷。因为在利用cTnT进行调整后，miRNA与预后指标丧失相关性，这表明miRNA并不能提高对预后预测的准确性。同时，在一项长达6年、包括510例AMI患者的随访中，Goretti等[45]也得出相似结论，认为miR-208b、miR499以及cTnT都不能准确预测6年的AMI患者死亡率。这些结果提示miRNA可作为AMI的预后指标这一猜想仍需要进一步的研究。

2 miRNA治疗心肌梗死的新进展

miRNA与心血管疾病的发展密切相关，尤其在调控心肌细胞凋亡和增殖[46-47]、血管再生[48]、祖细胞和干细胞功能修复[49]等方面都扮演着重要的角色。

由于miRNA对心肌的生长发育及凋亡都起着重要作用，将miRNA应用于心肌梗死的治疗成为目前研究的热点。其中，miR-34家族在心肌的发育中尤为重要。在小鼠模型中，通过抑制miR-34能够改善心脏功能，改善心肌重构及心肌纤维化。心肌纤维化是心肌梗死后心脏衰竭发展的关键因素，因此，改善心肌纤维化对于延缓心肌梗死进程和改善心衰具有重要作用[50-51]。而miR-24通过抑制B细胞慢性淋巴细胞白血病/淋巴瘤-2样11(B-cell lymphoma 2 like 11, BCL2L11)实现促心肌凋亡作用。因此，miR-24的抑制也能起到治疗心肌梗死的作用[52]。除此之外，miR-15家族[53]、miR-214[54]、miR-155[55]、miR-320[56]等都相继被报道在心肌纤维化的调控及血管再生方面扮演重要角色。miR-15家族能够通过下调烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide, NAD)依赖的沉默信息调节因子1(silent information regulator 1, SIRT 1)蛋白诱导心肌细胞凋亡[57]；同时，抑制miR-15能够诱导细胞周期检测点激酶基因1，(checkpoint kinase 1, Chk 1)的形成进而促进心肌细胞增殖[58]。miR-15还能通过抑制内皮细胞功能发挥抗血管生成作用[59]。但也有研究[57]认为，miRNA治疗存在诸多问题，如miRNA在治疗心肌梗死时，有可能促进其他疾病(如癌症等)的发展进程；同时，miRNA的疗法也可能引起不良反应。尽管多项研究揭示miRNA在AMI进程中发挥调控作用，miRNA治疗仍需要进一步的机制研究和动物实验来证实。

3 miRNA在临床应用中面临的挑战

miRNA可作为新型的AMI生物标志物，但目前仍有以下问题需要解决：(1)检测技术问题。miRNA在血清和血浆中水平低、易受蛋白质等杂质影响、检测时标准化方法的选择不确定，这些因素使miRNA不易被准确测量[60]。(2)在miRNA的临床研究中，通常使用 ROC来评估miRNA的准确度、特异度和灵敏度。然而，ROC曲线在小样本的研究中可能并不具有说服力，因此需要更大样本的研究来证实[61]。(3)若要将miRNA作为一种新型的生物标志物，有必要严格地定义该指标相应时间内具体的浓度范围来作为正常值或阈值。然而，miRNA在AMI患者中释放入血的确切时间尚无定论[7]。同时，由于miRNA含量太低、相对分子质量太小，不易测得其绝对浓度[62]。(4)肝素以及一些抗血小板药物的使用可能会影响PCR及某些特定miRNA表达，进而影响这些miRNA的测定。(5)与传统标志物cTnT相比，miRNA的测量更加耗时，同时费用也更加昂贵[63]。(6)研究[64]提示，有时候1种miRNA准确性并不高；而与单一miRNA相比，多种miRNA联合使用，对于AMI的诊断可能会更加准确。这些问题都给miRNA的实用性带来挑战，miRNA的研究仍然需要从检测技术、机制实验以及临床研究等多方面考量。

综上所述，无论在动物模型还是临床研究中都发现，miRNA可以作为一种新型的生物标志物，用来诊断AMI。同时，miRNA还显示出与AMI预后相关的特性。miRNA在调控心肌细胞增殖、凋亡、血管再生等方面的重要作用为治疗AMI提供了新的途径。然而，目前对miRNA的研究尚不全面，仍然存在诸多问题，这也提示需要更多的基础和临床研究支持。

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Recent progress on microRNA in diagnosis and treatment of myocardial infarction

WANG Zi, LÜ Qian-zhou, LI Xiao-ye*

Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai 200032, China

MicroRNAs (micro-ribonucleic acid, miRNAs) are small non-coding RNA molecules, which play an important role in regulating gene transcription. Recent research has found that miRNAs can be used as a new biomarker because of being involved in the progresses of cardiomyocyte development, proliferation and apoptosis. They play an important role in the early diagnosis, prognosis and treatment of acute myocardial infarction. However, there are still many problems and challenges in detection technology, mechanism research and clinical trials of miRNAs.

microRNA; acute myocardial infarction; cardiovascular diseases; biomarkers

2017-02-28接受日期2017-04-26

王 梓，博士生. E-mail: 332654052@qq.com

*通信作者(Corresponding author). Tel: 021-64041990, E-mail: 13916088938@163.com

10.12025/j.issn.1008-6358.2017.20170153

R 542.2+2

A

[本文编辑] 廖晓瑜， 贾泽军