MicroRNA在心肌梗死臨床診療中的應(yīng)用進(jìn)展

王 梓， 呂遷洲， 李曉燁

復(fù)旦大學(xué)附屬中山醫(yī)院藥劑科，上海 200032

·綜述·

MicroRNA在心肌梗死臨床診療中的應(yīng)用進(jìn)展

王 梓， 呂遷洲， 李曉燁*

復(fù)旦大學(xué)附屬中山醫(yī)院藥劑科，上海 200032

微小RNA(micro-ribonucleic acid, microRNA/miRNA)是一種小的非編碼RNA，在調(diào)控基因的轉(zhuǎn)錄過程中起著重要作用。近年來研究發(fā)現(xiàn)，miRNA參與心肌細(xì)胞發(fā)育、增殖、凋亡等進(jìn)程，可作為一種新型的生物標(biāo)志物，在急性心肌梗死的早期診斷、預(yù)后甚至治療等方面扮演重要角色。然而，目前miRNA在檢測技術(shù)、機(jī)制研究及臨床試驗方面仍面臨諸多問題和挑戰(zhàn)。本文就上述系列內(nèi)容作一綜述。

microRNA；急性心肌梗死；心血管疾?。簧飿?biāo)志物

微小RNA(micro-ribonucleic acid, microRNA/miRNA)是一種包含約20～23個核苷酸的短鏈非編碼RNA，在調(diào)控基因轉(zhuǎn)錄的過程中扮演著重要角色。1993年，Victor Ambros和Gary Ruvkin實驗室最早在線蟲中證實了miRNA的存在[1]。miRNA通常由細(xì)胞外轉(zhuǎn)運(yùn)體(如脂蛋白等)轉(zhuǎn)運(yùn)，也可以微泡或微囊的形式包裹起來，因此miRNA能夠穩(wěn)定地存在于血液循環(huán)中。據(jù)估計，人類基因組編碼了1 000多種miRNA，這些miRNA調(diào)控著約1/3的基因[2]。近年來研究[3]發(fā)現(xiàn)，這些miRNA調(diào)控著許多細(xì)胞進(jìn)程，如細(xì)胞增殖、分化、發(fā)育和凋亡。同時，在臨床上，miRNA不僅在腫瘤中扮演生物標(biāo)志物的角色，也能發(fā)揮對心血管疾病的診療作用[4-5]。

1 miRNA作為心肌梗死診斷及預(yù)后的生物標(biāo)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，明確的早期診斷在AMI的治療中至關(guān)重要。長期以來，心肌肌鈣蛋白T(cardiac troponin T, cTnT)或高敏心肌肌鈣蛋白T(high-sensitivity cardiac troponin, hs-cTnT)是診斷AMI的金標(biāo)準(zhǔn)[6]。然而，cTnT或hs-cTnT的特異性較低，一些其他疾病(如高血壓危象、腎衰、心衰等)也會引起cTnT升高，容易誤診。另外，cTnT或hs-cTnT的升高往往出現(xiàn)在AMI發(fā)生后3～6 h，可能延誤診斷[7]。因此，尋找更加敏感、更加特異的生物標(biāo)志物，盡早診斷AMI，能夠降低患者死亡率。近年來的研究[8-9]顯示，一些miRNA在AMI中會發(fā)生改變，提示其可作為新型的生物標(biāo)志物。

1.1 miRNA在心肌梗死早期診斷中的價值 研究[10-11]表明，多種miRNA水平在心肌梗死早期階段出現(xiàn)明顯變化，其中4種心源性和肌源性的miRNA研究最為廣泛：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達(dá)，包括2種亞型，miR-1-1和miR-1-2，分別由染色體18和染色體20的不同基因編碼。miR-1通過抑制間隙連接蛋白(gap junction alpha-1 protein, GJA 1)和鉀內(nèi)向整流通道超家族J成員2(potassium inwardly rectifying channel subfamily J member 2, KCNJ 2)調(diào)節(jié)心肌再生和分化[12]。在心肌細(xì)胞壞死模型中，miR-1可以穩(wěn)定地維持至少24 h。而在大鼠AMI模型中，miR-1迅速釋放入血，并在AMI后6 h達(dá)到峰值[13]。在一項包含56例AMI患者和28例非AMI患者的研究中，AMI患者血漿中miR-1明顯增高，并且在第14天回到基線[14]。另外，Ai等[15]在對159例患者的研究中發(fā)現(xiàn)，AMI組患者血漿中miR-1水平顯著高于非AMI組，且該指標(biāo)與年齡、性別、血壓等無關(guān)，與QRS波相關(guān)。同時，在非AMI患者和AMI患者血漿中，miR-1的受試者工作特征曲線(receiver operating characteristic curve, ROC)下面積(area under curve，AUC)為0.774 0。這提示在臨床上可以將miR-1作為一種獨(dú)立的生物標(biāo)志物，通過檢測血漿中的miR-1含量，能及早并且較準(zhǔn)確地提示AMI，有助于對AMI患者進(jìn)行早期治療。

miR-133在心肌、骨骼肌及平滑肌中都有表達(dá)，包括miR-133a和miR-133b 兩種，其中miR-133a與miR-1處于相同的染色體位點，并對平滑肌細(xì)胞的調(diào)節(jié)起著關(guān)鍵作用[16]。在對斑馬魚的研究中，Yin等[17]發(fā)現(xiàn)，miR-133可能通過作用于靶點GJA 1進(jìn)而抑制心肌增殖。在小鼠的AMI模型中，血漿中的miR-133水平明顯增高并且在6 h即達(dá)到峰值[11]。在1項包含了13例AMI患者、176例心絞痛患者及127例對照組中，AMI患者血漿中的miR-133a呈時間依賴性地增加到72.1倍。同時，研究發(fā)現(xiàn)miR-133a在冠脈狹窄程度不同的患者中含量存在顯著差別，提示臨床上可以通過測量miR-133a水平來預(yù)測冠脈阻塞的嚴(yán)重性[18]。Peng等[19]研究了186例患者，其中包括76例AMI患者，也發(fā)現(xiàn)患者血漿中的miR-133與AMI的發(fā)生相關(guān)，并指出其可能改善AMI預(yù)測風(fēng)險的分層效果。由于miR-1和miR-133a在心肌和骨骼肌中均高表達(dá)，因此相比于miR-208，這2種miRNA在診斷心肌損傷的特異性方面具有一定局限性。因此，在利用miR-1和miR-133a診斷AMI時，應(yīng)排除骨骼肌損傷[20]。

miR-208主要在心肌中表達(dá)，由α肌球蛋白重鏈(myosin heavy light, MYH)編碼。miR-208包括miR-208a和miR-208b，分別由MYH6和MYH7編碼[21]。miR-208a在心肌梗死模型的組織和血清中的高表達(dá)可能是由cAMP/PKA信號通路介導(dǎo)的[22]。在小鼠AMI模型中，miR-208a在心梗后4 h和24 h分別升高36倍和51倍[23]。同時，AMI患者血漿中的miR-208水平也比正常人明顯升高[24]。除此之外，Han等[25]還發(fā)現(xiàn)在發(fā)生2～3處血管狹窄的AMI患者中，血漿miR-208水平明顯高于僅發(fā)生1處血管狹窄的患者。另外，AMI患者在PCI術(shù)后，miR-208水平也會明顯降低。Wang等[10]研究發(fā)現(xiàn)，非AMI患者血漿中幾乎測不到miR-208a，但在90.9%的AMI患者中都能檢測到該指標(biāo)。同時，用miR-208a診斷AMI時，AUC為0.965，而傳統(tǒng)標(biāo)志物cTnI的AUC為0.987，說明miR-208a能夠準(zhǔn)確地診斷AMI。這些研究都表明血漿中miR-208與心肌梗死程度密切相關(guān)，可能作為新型的AMI生物標(biāo)志物。

miR-499也是一種心肌特異性的miRNA，由MYH7B基因編碼[26]。在大鼠心梗模型中，血漿中miR-499水平顯著升高。同時，AMI患者出現(xiàn)胸痛癥狀12 h后，miR-499可達(dá)到峰值，相比于miR-1和miR-133較延緩[11]。在一項包含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患者血漿中miR-499也明顯升高[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為0.70，而miR-499-5p的AUC為0.86。這說明血液中升高的miR-499-5p比hs-cTnT能夠更準(zhǔn)確地預(yù)測患者1年內(nèi)的死亡風(fēng)險。

除了miR-1、miR-133、miR-208和miR-499之外，研究顯示其他的miRNA也可作為心肌梗死的生物標(biāo)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。同時，研究也表明，聯(lián)合2種或多種miRNA能夠增加AUC值，可能會有助于提高診斷敏感性和特異性[39-40]。隨著基因芯片技術(shù)的發(fā)展及miRNA含量檢測技術(shù)的優(yōu)化，miRNA作為心肌梗死生物標(biāo)志物的前景值得期待。

1.2 microRNA在心肌梗死預(yù)后中的價值 miRNA除了在AMI的早期診斷方面具有一定價值外，在AMI的預(yù)后預(yù)測上也能發(fā)揮作用。在一項對359例AMI患者的6個月隨訪中發(fā)現(xiàn)，心室重構(gòu)患者血漿中miR-208b和miR-34a水平明顯升高[41]。另外，Dong等[42]證實，miR-145是一種獨(dú)立的心血管事件預(yù)測因子，能夠作為心肌梗死長期預(yù)后的生物標(biāo)志物。另外一項研究[43]中，研究人員對424例心肌梗死的患者進(jìn)行30 d隨訪，同時，用左心室射血分?jǐn)?shù)(left ventricular ejection fraction, LVEF)評估左心室收縮功能。結(jié)果顯示血漿中增加的miR-208b和miR-499與增加的死亡風(fēng)險和心衰風(fēng)險密切相關(guān)。然而，一些研究者也對miRNA與AMI預(yù)后的相關(guān)性表示質(zhì)疑。Gidl?f等[43]和Widera等[44]認(rèn)為，將這些miRNA作為預(yù)后指標(biāo)仍有待商榷。因為在利用cTnT進(jìn)行調(diào)整后，miRNA與預(yù)后指標(biāo)喪失相關(guān)性，這表明miRNA并不能提高對預(yù)后預(yù)測的準(zhǔn)確性。同時，在一項長達(dá)6年、包括510例AMI患者的隨訪中，Goretti等[45]也得出相似結(jié)論，認(rèn)為miR-208b、miR499以及cTnT都不能準(zhǔn)確預(yù)測6年的AMI患者死亡率。這些結(jié)果提示miRNA可作為AMI的預(yù)后指標(biāo)這一猜想仍需要進(jìn)一步的研究。

2 miRNA治療心肌梗死的新進(jìn)展

miRNA與心血管疾病的發(fā)展密切相關(guān)，尤其在調(diào)控心肌細(xì)胞凋亡和增殖[46-47]、血管再生[48]、祖細(xì)胞和干細(xì)胞功能修復(fù)[49]等方面都扮演著重要的角色。

由于miRNA對心肌的生長發(fā)育及凋亡都起著重要作用，將miRNA應(yīng)用于心肌梗死的治療成為目前研究的熱點。其中，miR-34家族在心肌的發(fā)育中尤為重要。在小鼠模型中，通過抑制miR-34能夠改善心臟功能，改善心肌重構(gòu)及心肌纖維化。心肌纖維化是心肌梗死后心臟衰竭發(fā)展的關(guān)鍵因素，因此，改善心肌纖維化對于延緩心肌梗死進(jìn)程和改善心衰具有重要作用[50-51]。而miR-24通過抑制B細(xì)胞慢性淋巴細(xì)胞白血病/淋巴瘤-2樣11(B-cell lymphoma 2 like 11, BCL2L11)實現(xiàn)促心肌凋亡作用。因此，miR-24的抑制也能起到治療心肌梗死的作用[52]。除此之外，miR-15家族[53]、miR-214[54]、miR-155[55]、miR-320[56]等都相繼被報道在心肌纖維化的調(diào)控及血管再生方面扮演重要角色。miR-15家族能夠通過下調(diào)煙酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide, NAD)依賴的沉默信息調(diào)節(jié)因子1(silent information regulator 1, SIRT 1)蛋白誘導(dǎo)心肌細(xì)胞凋亡[57]；同時，抑制miR-15能夠誘導(dǎo)細(xì)胞周期檢測點激酶基因1，(checkpoint kinase 1, Chk 1)的形成進(jìn)而促進(jìn)心肌細(xì)胞增殖[58]。miR-15還能通過抑制內(nèi)皮細(xì)胞功能發(fā)揮抗血管生成作用[59]。但也有研究[57]認(rèn)為，miRNA治療存在諸多問題，如miRNA在治療心肌梗死時，有可能促進(jìn)其他疾病(如癌癥等)的發(fā)展進(jìn)程；同時，miRNA的療法也可能引起不良反應(yīng)。盡管多項研究揭示miRNA在AMI進(jìn)程中發(fā)揮調(diào)控作用，miRNA治療仍需要進(jìn)一步的機(jī)制研究和動物實驗來證實。

3 miRNA在臨床應(yīng)用中面臨的挑戰(zhàn)

miRNA可作為新型的AMI生物標(biāo)志物，但目前仍有以下問題需要解決：(1)檢測技術(shù)問題。miRNA在血清和血漿中水平低、易受蛋白質(zhì)等雜質(zhì)影響、檢測時標(biāo)準(zhǔn)化方法的選擇不確定，這些因素使miRNA不易被準(zhǔn)確測量[60]。(2)在miRNA的臨床研究中，通常使用 ROC來評估m(xù)iRNA的準(zhǔn)確度、特異度和靈敏度。然而，ROC曲線在小樣本的研究中可能并不具有說服力，因此需要更大樣本的研究來證實[61]。(3)若要將miRNA作為一種新型的生物標(biāo)志物，有必要嚴(yán)格地定義該指標(biāo)相應(yīng)時間內(nèi)具體的濃度范圍來作為正常值或閾值。然而，miRNA在AMI患者中釋放入血的確切時間尚無定論[7]。同時，由于miRNA含量太低、相對分子質(zhì)量太小，不易測得其絕對濃度[62]。(4)肝素以及一些抗血小板藥物的使用可能會影響PCR及某些特定miRNA表達(dá)，進(jìn)而影響這些miRNA的測定。(5)與傳統(tǒng)標(biāo)志物cTnT相比，miRNA的測量更加耗時，同時費(fèi)用也更加昂貴[63]。(6)研究[64]提示，有時候1種miRNA準(zhǔn)確性并不高；而與單一miRNA相比，多種miRNA聯(lián)合使用，對于AMI的診斷可能會更加準(zhǔn)確。這些問題都給miRNA的實用性帶來挑戰(zhàn)，miRNA的研究仍然需要從檢測技術(shù)、機(jī)制實驗以及臨床研究等多方面考量。

綜上所述，無論在動物模型還是臨床研究中都發(fā)現(xiàn)，miRNA可以作為一種新型的生物標(biāo)志物，用來診斷AMI。同時，miRNA還顯示出與AMI預(yù)后相關(guān)的特性。miRNA在調(diào)控心肌細(xì)胞增殖、凋亡、血管再生等方面的重要作用為治療AMI提供了新的途徑。然而，目前對miRNA的研究尚不全面，仍然存在諸多問題，這也提示需要更多的基礎(chǔ)和臨床研究支持。

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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

[本文編輯] 廖曉瑜， 賈澤軍