李歆躍(綜述)，楊　巍(審校)

(哈爾濱醫(yī)科大學(xué)附屬第一醫(yī)院心內(nèi)六科，哈爾濱 150001)

心臟重構(gòu)中微RNA的作用

李歆躍△(綜述)，楊巍※(審校)

(哈爾濱醫(yī)科大學(xué)附屬第一醫(yī)院心內(nèi)六科，哈爾濱 150001)

摘要：心臟重構(gòu)是各類心血管疾病的重要進(jìn)程之一，包括心肌梗死、瓣膜疾病、心肌炎、擴(kuò)張型心肌病、心房顫動(dòng)和心力衰竭等。多項(xiàng)研究發(fā)現(xiàn)，微RNA(miRNA)與此過(guò)程息息相關(guān)，并且在體內(nèi)和體外實(shí)驗(yàn)?zāi)Ｐ椭卸甲C實(shí)了miRNA廣泛地參與此進(jìn)程。臨床上，miRNA已作為潛在的診斷指標(biāo)和治療靶點(diǎn)被重視。該文就近年的熱點(diǎn)及被重點(diǎn)研究的幾種miRNA進(jìn)行綜述。

關(guān)鍵詞：心臟重構(gòu)；微RNA；纖維化；心肌肥大

微RNA(microRNA，miRNA)是一組高度保守、長(zhǎng)度約22個(gè)核苷酸的內(nèi)源性非編碼RNA。動(dòng)物細(xì)胞核內(nèi)，編碼miRNA的基因首先在RNA聚合酶2的作用下發(fā)生轉(zhuǎn)錄，形成長(zhǎng)度約為幾百個(gè)核苷酸的初級(jí)轉(zhuǎn)錄物pri-miRNA，經(jīng)核糖核酸酶Ⅲ家族的Drosha酶加工成pre-miRNA并轉(zhuǎn)運(yùn)到核外；在核外經(jīng)Dicer酶加工為成熟的miRNA并與之形成RNA誘導(dǎo)沉默復(fù)合體；RNA誘導(dǎo)沉默復(fù)合體與靶基因信使RNA(mRNA)非編碼區(qū)種子序列結(jié)合，使其降解或沉默表達(dá)，從而起到調(diào)控基因和蛋白的作用[1-3]。現(xiàn)就心臟重構(gòu)中miRNA的作用進(jìn)行綜述。

1心臟重構(gòu)的病理過(guò)程

心臟重構(gòu)是心臟在對(duì)抗外界因素所致的壓力和阻力時(shí)為了維持穩(wěn)態(tài)而進(jìn)行自身調(diào)節(jié)的適應(yīng)性過(guò)程，該過(guò)程存在于離子、基因、細(xì)胞和細(xì)胞外等多個(gè)水平[4]。如果所致壓力和阻力作用持續(xù)存在，這種過(guò)程可發(fā)展為不可逆作用[5]，同時(shí)在細(xì)胞和細(xì)胞外水平可發(fā)生凋亡、壞死和纖維化等變化。心臟重構(gòu)過(guò)程分為兩種形式，即組織重構(gòu)和電重構(gòu)[6]。

1.1組織重構(gòu)心臟成纖維細(xì)胞是心臟組織中數(shù)量最多的細(xì)胞，其在調(diào)節(jié)心臟細(xì)胞外基質(zhì)代謝方面起重要作用。心臟間質(zhì)細(xì)胞合成的主要物質(zhì)是膠原，其可被激素、生長(zhǎng)因子、激酶、血流動(dòng)力學(xué)因素、調(diào)節(jié)蛋白(如金屬基質(zhì)蛋白及其抑制物)所控制和調(diào)節(jié)[7-8]。細(xì)胞外基質(zhì)的穩(wěn)態(tài)被膠原合成和分解的動(dòng)態(tài)平衡所維持著。膠原的生物合成在轉(zhuǎn)錄水平被成纖維生長(zhǎng)因子所調(diào)控，尤其是轉(zhuǎn)化生長(zhǎng)因子β(transforming growth factor β,TGF-β)，其通過(guò)刺激結(jié)締組織生長(zhǎng)因子而強(qiáng)烈地誘導(dǎo)細(xì)胞外基質(zhì)的合成；膠原的分解主要依靠金屬基質(zhì)蛋白超家族[9]。組織纖維化伴隨著退化心肌動(dòng)態(tài)的修補(bǔ)和替換。心肌肥大是心臟組織重構(gòu)的另一特點(diǎn)，它可促進(jìn)心臟功能障礙、導(dǎo)致充血性心力衰竭甚至猝死等惡性事件[10]。心肌肥大這一過(guò)程通過(guò)基因被重新激活，繼而通過(guò)細(xì)胞內(nèi)信號(hào)通路影響心肌細(xì)胞正常表達(dá)蛋白的轉(zhuǎn)錄而實(shí)現(xiàn)[11]。已證實(shí)多條分子通路參與其中，包括腎素-血管緊張素-醛固酮系統(tǒng)、腎上腺素能系統(tǒng)、腦鈉肽以及細(xì)胞骨架蛋白、白細(xì)胞介素6細(xì)胞因子家族、細(xì)胞外信號(hào)調(diào)節(jié)激酶1/2信號(hào)通路、組蛋白乙酰化作用和鈣離子介導(dǎo)的調(diào)控機(jī)制等[12]。

1.2電重構(gòu)心臟擁有隨時(shí)調(diào)節(jié)其功能從而快速適應(yīng)身體需要的潛能。在面對(duì)快速變化的外界環(huán)境時(shí)，心肌細(xì)胞需要有快速增加或減少其離子通道的能力；在心房或者心室，電重構(gòu)都可發(fā)生；最初的代償期里心臟尚能維持其電行為，一旦失代償就會(huì)引發(fā)進(jìn)一步的泵衰竭或惡性心律失常[13-14]。心臟的電活動(dòng)由一系列的離子通道活動(dòng)所協(xié)調(diào)完成；控制離子跨膜轉(zhuǎn)運(yùn)的跨膜蛋白和轉(zhuǎn)運(yùn)蛋白對(duì)維持心臟自主節(jié)律、電傳導(dǎo)以及膜的復(fù)極化很重要；通道疾病主要由基因水平異常所致的離子通道功能障礙所引起[15-16]。

2心臟重構(gòu)中涉及的miRNAs

2.1miR-133miR-133是在人類心臟中最廣泛表達(dá)的miRs，其家族包括miR-133a-1、miR-133a-2、miR-133b三個(gè)成員；在體內(nèi)過(guò)表達(dá)miR-133被認(rèn)為可阻止心臟重構(gòu)的發(fā)生[17]。最新的研究顯示，在肌組織的發(fā)生和成熟中，miR-133直接調(diào)控N端結(jié)合多聚嘧啶束蛋白；N端結(jié)合多聚嘧啶束蛋白和其同系物參與調(diào)節(jié)許多肌組織特異的外顯子(如肌鈣蛋白T和原肌球蛋白)；miR-133還聯(lián)合miR-1通過(guò)調(diào)節(jié)嚴(yán)格肌源性轉(zhuǎn)錄因子血漿應(yīng)答因子和去乙?；?對(duì)骨骼肌原細(xì)胞增殖和分化進(jìn)行調(diào)控[10]。在miR-133的雙重突變型小鼠中觀察到，控制細(xì)胞周期的基因異常，且平滑肌基因組被異常激活，這可能可以歸因于其靶基因的上調(diào)(如血漿應(yīng)答因子、細(xì)胞周期調(diào)節(jié)蛋白D2)[2]。在大鼠的心肌細(xì)胞中發(fā)現(xiàn)了miR-133的抗凋亡作用[10]。目前對(duì)miR-133的研究存有爭(zhēng)議[18]。在兩種嚙齒類動(dòng)物的左心室肥大模型以及9例心力衰竭受試者中證實(shí)，成熟的miR-133減少；同樣，細(xì)胞實(shí)驗(yàn)中下調(diào)的miR-133可以引起心肌肥大相關(guān)基因的表達(dá)；但有實(shí)驗(yàn)顯示，在缺失miR-133a的轉(zhuǎn)基因小鼠中心臟表型正常；此外，在主動(dòng)脈縮窄術(shù)后，miR-133a雖下降了50%，但3周后又恢復(fù)正常[19]。這提示miR-133a在心肌肥大過(guò)程中只起到了短暫和不穩(wěn)定的作用。還有實(shí)驗(yàn)顯示，在小鼠體內(nèi)過(guò)表達(dá)miR-133沒(méi)有起到任何作用，而且防止miR-133下調(diào)也不能減輕心肌肥大[18]。這些相反的數(shù)據(jù)使得對(duì)miR-133在心肌肥大中真正作用的研究更有必要。

2.2miR-1miR-1雖然被預(yù)測(cè)靶向調(diào)控很多基因，但經(jīng)確認(rèn)的目前只有HAND2(heart and neural crest derivatives expressed transcript 2)基因。不像miR-133，miR-1在心臟重構(gòu)中所調(diào)控的mRNAs是一致公認(rèn)的[20]。在新生大鼠的心肌細(xì)胞和未受損的成人心肌中觀察到，其陰性調(diào)節(jié)肌細(xì)胞增強(qiáng)因子2a、GATA4(gata binding protein 4)，通過(guò)鈣神經(jīng)素-NFAT(calcineurin-NFAT)通路減弱了引起心肌肥大時(shí)鈣依賴通路參與的必要性；另一個(gè)抑制心肌細(xì)胞肥大的機(jī)制是通過(guò)胰島素生長(zhǎng)因子通路實(shí)現(xiàn)的，miR-1可以抑制胰島素生長(zhǎng)因子1和胰島素生長(zhǎng)因子1R的轉(zhuǎn)錄[21]。在心肌細(xì)胞凋亡方面，miR-1被認(rèn)為起到拮抗miR-133的作用；在大鼠凋亡的心肌細(xì)胞中，miR-1顯著升高，在熱激蛋白60和熱激蛋白70的3′非轉(zhuǎn)錄區(qū)域可能存在單一的被miR靶向調(diào)控的序列[22-24]。有實(shí)驗(yàn)發(fā)現(xiàn)，不論在正常還是心肌梗死后大鼠體內(nèi)應(yīng)用miR-1都可引發(fā)心律失常，說(shuō)明miR-1也參與了電重構(gòu)過(guò)程；改變miR-1的水平可能是致心律失常作用的觸發(fā)器[25]。

2.3miR-21miR-21是在心臟重構(gòu)中表達(dá)水平上調(diào)最高的miR，但其確切的機(jī)制存在爭(zhēng)議且目前尚不明確。在心肌肥大方面，有實(shí)驗(yàn)發(fā)現(xiàn)，用膽固醇修飾的antagomiRs剔除miR-21后能有效減輕心臟纖維化和心肌肥大[26]；與其相反，在另一個(gè)實(shí)驗(yàn)中，通過(guò)鎖基因技術(shù)剔除miR-21后引起了心肌細(xì)胞的肥大[27]。最近有學(xué)者認(rèn)為，由于心臟對(duì)小片段核酸的快速清除作用，缺少鎖基因技術(shù)的antagomiRs的應(yīng)用需要進(jìn)一步被解釋[26-28]。miR-21在纖維化方面的作用已經(jīng)基本明確，PTEN(Phosphatase and tensin homologue)和SPRY1(sprouty1)被認(rèn)為是miR-21的靶基因；miR-21通過(guò)抑制SPRY1增進(jìn)了胞外信號(hào)調(diào)節(jié)激酶/絲裂原活化蛋白激酶通路的作用；在心臟成纖維細(xì)胞中，上調(diào)miR-21可以通過(guò)增強(qiáng)ERK/MAPK通路致成纖維細(xì)胞增殖，從而引起心臟重構(gòu)和纖維化[29]。

2.4miR-208實(shí)驗(yàn)觀察到，過(guò)表達(dá)miR-208a可以充分激活鈣神經(jīng)素通道，并通過(guò)抑制甲狀腺激素相關(guān)蛋白1引起心肌肥大[30]。在小鼠中，筒箭毒堿和甲狀腺激素相關(guān)蛋白1的相繼失活與心肌肥大關(guān)系密切[31]。在剔除miR-208a基因的小鼠中，抗纖維化的分子在轉(zhuǎn)錄水平大量表達(dá)[32]。另外一個(gè)重要的發(fā)現(xiàn)是，在擴(kuò)張型心肌病中，高水平的miR-208表達(dá)多與較差的預(yù)后相關(guān)[30]。這提示miR-208可以作為疾病預(yù)后和心力衰竭進(jìn)展的預(yù)測(cè)指標(biāo)。

2.5miR-29miR-29在心臟成纖維細(xì)胞中廣泛表達(dá)，與miR-133和miR-30一起被認(rèn)為是與纖維化關(guān)聯(lián)最密切的miRNAs。其可靶向調(diào)控許多與細(xì)胞外基質(zhì)相關(guān)的mRNAs(包括彈性蛋白、原纖維蛋白1、膠原蛋白Ⅰ、膠原蛋白Ⅲ等)；在體內(nèi)下調(diào)miR-29能顯著上調(diào)上述蛋白，并能引起大量的膠原沉積[33]。研究發(fā)現(xiàn)，心肌梗死后鹽酸普萘洛爾給藥組瘢痕組織miR-29增多，這可能是β受體阻滯劑能改善心肌梗死預(yù)后的可能原因之一[33-35]。

2.6其他高通量實(shí)驗(yàn)顯示，許多miRNAs在心臟重構(gòu)進(jìn)程中發(fā)生了變化。其中，在小鼠心臟中過(guò)表達(dá)miR-195引起了嚴(yán)重的心肌肥大；另外，上調(diào)miR-24、miR-214、miR-23a也引起了心肌肥大；miR-328通過(guò)靶向調(diào)控L型鈣通道參與逆轉(zhuǎn)心房電重構(gòu)的作用；miR-30也被預(yù)測(cè)參與阻斷了L型鈣通道；而miR-499和miR-199a在抑制心肌凋亡方面起到重要作用；與之相反，miR-320發(fā)揮了刺激心肌細(xì)胞凋亡的作用[36-41]。

3小結(jié)

miRNAs的生物學(xué)研究是一個(gè)相對(duì)新的研究領(lǐng)域，近幾年對(duì)miRNAs的研究急速發(fā)展。從miRNAs擬似物，到反義核苷酸抑制序列，再到antagomiR和鎖基因技術(shù)的應(yīng)用，使得體內(nèi)miRNAs的研究成為可能[42]。近期在小鼠模型中數(shù)目可觀的研究顯示了miRNAs靶基因治療的可行性。由于一種miRNAs可調(diào)控上百種基因，人們?cè)鴵?dān)憂其靶基因治療所帶來(lái)的不可預(yù)知的不良反應(yīng)，使其前景受限。目前一種miRMask被設(shè)計(jì)出來(lái)，其可準(zhǔn)確地結(jié)合目標(biāo)mRNA而防止miRNAs與其他未知靶基因結(jié)合[43]。與其相反，同時(shí)靶向多種miRNAs的技術(shù)—miRNAs海綿技術(shù)，也被發(fā)明出來(lái)[44]。未來(lái)的研究應(yīng)以miRNAs靶基因治療為目標(biāo)，更深入地了解miRNAs是如何整合并參與到疾病中去的[45-48]。為了更好地靶向患病器官，針對(duì)不同的細(xì)胞類型、組織或器官，特異的miRNAs研究也是挑戰(zhàn)之一。雖然還有很長(zhǎng)的路要走，但理論上miRNAs仍是征服心臟重構(gòu)的有力武器。

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The Role of MicroRNAs in the Cardiac Remodeling

LIXin-yue,YANGWei.

(DepartmentSixofCardiology,theFirstAffiliatedHospitalofHarbinMedicalUniversity,Harbin150001,China)

Abstract:Cardiac remodeling is the key process in cardiovascular diseases including myocardial infarction,valvular disease,myocarditis,dilated cardiomyopathy,atrial fibrillation and heart failure.Both in vitro and vivo models have proved that microRNAs play an important role in a wide range of processes.Clinically,miRNAs have been attached much attention as the potential diagnostic biomarkers and novel therapeutic target recently.Here is to make a review of the focal points and mostly studied miRNA in the recent years.

Key words:Cardiac remodeling; MicroRNAs; Fibrosis; Myocyte hypertrophy

收稿日期：2014-01-15修回日期：2014-07-30編輯：鄭雪

基金項(xiàng)目：國(guó)家自然科學(xué)基金(81271676)

doi：10.3969/j.issn.1006-2084.2015.04.003

中圖分類號(hào)：R541

文獻(xiàn)標(biāo)識(shí)碼：A

文章編號(hào)：1006-2084(2015)04-0582-03