吳 昊 周 甜 鄧巧莉綜述 胡家才審校

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微小核糖核酸對血管平滑肌細胞表型轉(zhuǎn)換影響的研究進展

吳 昊 周 甜 鄧巧莉綜述 胡家才*審校

血管平滑肌細胞(VSMC)作為血管中膜的主要構(gòu)成細胞，其功能作用與其表型變化密切相關(guān)。合成表型具有增生及遷移能力，是各種心血管及周圍血管病發(fā)生發(fā)展的主要病理基礎(chǔ)，而收縮表型對維持血管彈性和收縮功能至關(guān)重要。較多微小核糖核酸(microRNAS, miRNAS)可通過相關(guān)途徑和方式調(diào)控VSMC表型轉(zhuǎn)換，從而在機體病理生理變化中發(fā)揮重要作用。本文綜述涉及上述調(diào)節(jié)的miRNA研究的有關(guān)進展。

微小核糖核酸；血管平滑肌細胞；表型

血管平滑肌細胞(Vascular Smooth Muscle Cell, VSMC)是動脈中膜的組成部分之一，其收縮/舒張可調(diào)節(jié)血管張力，控制血壓。某些病理刺激，如血管炎性損傷、血流切應(yīng)力異常變化、內(nèi)皮生長因子增加等能引起VSMC表型轉(zhuǎn)換，使其由具有維持血管彈性、收縮功能的收縮表型(分化表型)向具有強大增殖及遷移能力的合成表型(未分化表型)變化[1]。VSMC表型轉(zhuǎn)化是機體生理功能維護和較多動脈病變?nèi)缪艹尚托g(shù)后、肺動脈高壓及動脈粥樣硬化等過程的關(guān)鍵步驟。已有研究[1-10]表明多種微小核糖核酸(MicroRNAs，miRNAs)具有調(diào)控VSMC表型轉(zhuǎn)換作用，該作用通過抑制靶向物的信使核糖核酸(Messenger RNA，mRNA)和/或蛋白轉(zhuǎn)錄，精確調(diào)節(jié)心血管系統(tǒng)的相關(guān)通路來實現(xiàn)。研究miRNA對VSMC表型轉(zhuǎn)化對認識血管疾病的發(fā)生機制具有重要意義。

1 miRNAs的產(chǎn)生和作用

miRNAs是一類19-25個堿基的內(nèi)源性非編碼RNA單鏈，成熟miRNA的產(chǎn)生，首先是在細胞核中由DNA轉(zhuǎn)錄生成較長的初級miRNA(Pri-miRNA)；Pri-miRNA在核內(nèi)經(jīng)Drosha酶剪切為70-100個核苷酸且具有發(fā)卡樣結(jié)構(gòu)的miRNA前體(Pre-miRNA)[11]；Pre-miRNA從胞核轉(zhuǎn)運到細胞質(zhì)中，再被Dicer酶剪切成19-25個核苷酸長度的miRNA雙鏈；最后雙鏈miRNA被組裝進RNA

誘導(dǎo)的沉默復(fù)合體(RNA-induced Silencing Complex,RISC)，通過堿基互補配對方式識別靶mRNA，并根據(jù)互補程度的不同降解靶mRNA或者阻遏靶mRNA的翻譯[12]。近10余年來的研究發(fā)現(xiàn)，miRNAs在RNA介導(dǎo)的轉(zhuǎn)錄后基因調(diào)控中起重要作用。 其通過與靶mRNA的 3’非轉(zhuǎn)錄端(Untranslated Region，UTR )的完全或不完全結(jié)合來降解mRNA或抑制其轉(zhuǎn)錄，負向調(diào)控基因表達。目前證實的人類miRNA有1 000余種，各種miRNA功能和作用不同，人類約60%的蛋白受miRNA調(diào)控[13, 14]。 對于VSMC，部分miRNA主要參與調(diào)節(jié)其合成和收縮。

2 VSMC的表型特點及其調(diào)節(jié)

VSMC可依據(jù)其功能及形態(tài)分為分化型和未分化型兩種表型。分化型是其成熟表型，分化程度較高，細胞多呈紡錘形，直徑一般2-5μm，長度通常在8-800μm。分化型VSMC胞漿內(nèi)的高爾基復(fù)合體和線粒體等具有合成功能的細胞器較少，但含有大量肌絲，表達如平滑肌肌動蛋白(α-Smooth Muscle Actin，α-SMA)、平滑肌肌球蛋白重鏈(Smooth Muscle Myosin Heavy Chain，SM-MHC)和鈣調(diào)節(jié)蛋白(Calponin)等，主要維持血管舒張與收縮能力，而增殖和遷移能力較差。未分化型VSMC分化程度較低，甚至未分化，多呈纖維母細胞樣，短小，胞漿內(nèi)肌絲、致密體和致密板極少，但含有大量高爾基復(fù)合體、線粒體和粗面內(nèi)質(zhì)網(wǎng)，因而具有良好的合成和分泌功能；主要合成和分泌膠原蛋白和細胞基質(zhì)金屬蛋白酶等細胞外基質(zhì)，參與血管壁的形成、修復(fù)、增殖和遷移[15]。

血小板源性生長因子(Platelet Derived Growth Factor, PDGF)及轉(zhuǎn)化生長因子-β(Transforming Growth Factor-β，TGF-β )均參與VSMC表型的轉(zhuǎn)化，其中PDGF被證實可以刺激VSMC有絲分裂、遷移及其表型從分化型向未分化型轉(zhuǎn)換[8, 16]。而TGF-β能通過刺激VSMC的某些特定基因組如α-SMA (也就是ACTA2)和轉(zhuǎn)凝蛋白(Smooth Muscle α，SM-22α)使得VSMC分化成熟[3, 17-19]。研究[20]表明敲除心肌蛋白或/及心肌蛋白相關(guān)轉(zhuǎn)錄因子(Myocardin Related Transcription Factors，MRTFs)的小鼠，因α-SMA和SM22α基因表達能力低下無法形成正常血管而不能存活，提示兩者與VSMC向分化表型轉(zhuǎn)換有關(guān)；體外實驗[21]也顯示，血清反應(yīng)因子(Serum Response Factor，SRF)聯(lián)合心肌蛋白及MRTFs可以促進胚胎干細胞向成熟VSMC分化。

3 miRNAs與VSMC表型

Dicer基因與miRNAs的產(chǎn)生密切相關(guān)，敲除Dicer基因小鼠，會出現(xiàn)胚胎發(fā)育停滯或無法形成正常新生血管[22]；同時會表現(xiàn)出嚴(yán)重低血壓、血管收縮功能減退及Calponin、a-SMA等與收縮相關(guān)蛋白的表達缺失[23]。表明miRNA對于VSMC既與合成表型有關(guān)，也與收縮表型關(guān)聯(lián)，從而影響VSMC的發(fā)生、成熟、分化及收縮功能。

3.1 miRNAs可使VSMC向未分化表型轉(zhuǎn)換

Chan等[18]報道受PDGF刺激小鼠，miR-24表達上調(diào)，可促使VSMC向未分化表型轉(zhuǎn)換，可能途徑為miR-24在PDGF誘導(dǎo)下靶向作用于內(nèi)質(zhì)網(wǎng)應(yīng)激因子(Tribble)TRB3，而抑制TRB3會使得將TGF-β配體信號從細胞核外傳導(dǎo)入核內(nèi)激活下游基因轉(zhuǎn)錄的Smad蛋白(Sma and Dgainst Decapentaplegic Protein)表達下調(diào)，進而影響骨形態(tài)蛋白(Bone Morphogenetic Protein，BMP)和TGF-β信號通路，促進VSMC增殖并向未分化型轉(zhuǎn)換。表明miR-24是PDGF調(diào)節(jié)VSMC表型的調(diào)控點，上調(diào)miR-24會使得VSMC向未分化型轉(zhuǎn)換。

Wang等[24]在體外培養(yǎng)的VSMC中發(fā)現(xiàn)了miR-31的表達，而且在增殖性VSMCs和具有新生內(nèi)膜的血管中miR-31表達更多，故認為miR-31可能使VSMC向未分化型轉(zhuǎn)換。還有研究顯示，在大鼠頸動脈球囊損傷時miR-31靶向作用于其下游產(chǎn)物大型腫瘤抑制基因2(Large Tumor Suppressor Homolog 2，LATS2)，而LATS2可抑制增殖細胞核抗原(Proliferating Cell Nuclear Antigen, PCNA)介導(dǎo)的VSMC增殖[25]。另有實驗證實，敲除miR-31可抑制PDGF介導(dǎo)的VSMC增殖[26]。且這兩種作用均與絲裂原激活蛋白激酶/胞外信號調(diào)節(jié)激酶(MAPK/ERK)抑制劑有關(guān)，因為MAPK/ERK是胞外細胞生長刺激和增殖信號的重要反應(yīng)路徑，所以MAPK/ERK/miR-31/LATS2/PCNA可能是VSMC向未分化型轉(zhuǎn)化的新信號通路。

miR-146a靶向作用于Kruppel樣因子4(Kruppel-like Factor 4,KLF4)的30非轉(zhuǎn)錄區(qū)，促進體外培養(yǎng)的細胞增殖[27]；轉(zhuǎn)染miR-146a反轉(zhuǎn)錄基因的球囊損傷大鼠中由KLF4介導(dǎo)的α-SMA和SM22α表達上調(diào)， 導(dǎo)致頸動脈內(nèi)膜及VSMC增生

能力明顯減弱[28]，同時發(fā)現(xiàn)KLF4和KLF5競爭性結(jié)合并調(diào)控miR-146a啟動子，但其作用相反，KLF4過表達會抑制miR-146a的轉(zhuǎn)錄水平[29]。表明miR-146a在調(diào)控VSMC向未分化表型轉(zhuǎn)換的同時也與KLF4形成負反饋環(huán)，調(diào)節(jié)這種轉(zhuǎn)換。 Zhang等[30]研究發(fā)現(xiàn)胰島素可促進VSMC增生，并且提高miR-208的表達，過表達miR-208能增加VSMC的基礎(chǔ)增生以及胰島素誘導(dǎo)的VSMC增生。盡管miR-208抑制劑對于VSMC的基礎(chǔ)增生沒有影響，但可減弱胰島素誘導(dǎo)的VSMC增生。進一步研究[2, 3]表明，miR-208還可靶向作用于細胞周期蛋白依賴性激酶相互作用蛋白/激酶抑制蛋白(Cyclin-Dependent Kinase Inhibitor, CDKN)家族的p21，加速細胞從G0/G1期向S期的轉(zhuǎn)變速度。說明胰島素及過表達miR-208都會增加VSMC增殖，同時均能抑制p21的作用，而使VSMC向未分化表型變換；但是在有miR-208抑制劑存在的情況下，胰島素不能發(fā)揮對p21的抑制作用。

Tallquist等[8]研究發(fā)現(xiàn)動脈損傷可能激活PDGF信號通路，使新生內(nèi)膜增生，同時抑制平滑肌特異性基因組如ACTA2和SM22的表達，促進VSMC由分化表型向未分化表型轉(zhuǎn)換。miR-221作為PDGF信號通路的表型調(diào)節(jié)器[13]，在已被PDGF刺激的原態(tài)VSMC中接受指令下調(diào)其靶向物酪氨酸激酶受體蛋白的一種c-Kit和CDKN家族的p27Kip1的表達水平。miR-211靶向下調(diào)p27Kip1是PDGF誘導(dǎo)VSMC增生的關(guān)鍵，同時降低c-Kit會抑制VSMC表達特異性收縮基因，從而有利于VSMC向未分化表型轉(zhuǎn)換。

3.2 miRNAs可使VSMC向分化表型轉(zhuǎn)換

部分miRNAs可促進VSMC進一步成熟、穩(wěn)定，轉(zhuǎn)換為收縮表型(分化表型)。

Xie等[31]研究表明，在胚胎干細胞向VSMC分化過程中miR-1表達水平穩(wěn)定升高，而將miR-1拮抗基因轉(zhuǎn)錄入VSMC后VSMC特異性標(biāo)志物以及成熟VSMC都會隨之減少，說明miR-1在胚胎干細胞源性VSMC分化過程中必不可少。Chen等[32]發(fā)現(xiàn)梭形VSMC(分化表型)miR-1的表達水平顯著高于上皮樣VSMC(未分化表型)，并且抑制VSMC增殖，但此作用可以被miR-1抑制劑拮抗。

Torella等[33]報道，miR-133在體內(nèi)及體外培養(yǎng)的VSMC中皆有豐富表達。當(dāng)血管受損，VSMC準(zhǔn)備增殖時，miR-133表達水平明顯降低，應(yīng)用轉(zhuǎn)染過表達miR-133可降低VSMC在體內(nèi)及體外的增殖及遷移；進一步研究發(fā)現(xiàn)miR-133抑制增殖作用主要通過特異性抑制轉(zhuǎn)錄因子Sp-1的表達，從而抑制VSMC增殖的基因表達。另外，miR-133可能下調(diào)受PDGF刺激后以及頸動脈球囊損傷后大鼠VSMC增殖。

Kim等[5]的實驗，通過激活骨形態(tài)發(fā)生蛋白4(Bone Morphogenetic Protein4，BMP4)信號通路使R-Smad 蛋白與miR-21的初級轉(zhuǎn)錄物pri-miR-21及Drosha結(jié)合，促進pri-miR-21向pre-miR-21轉(zhuǎn)化，進而增加miR-21的表達，而miR-21可下調(diào)PDGF介導(dǎo)VSMC遷移的重要調(diào)節(jié)因子細胞質(zhì)分裂付出蛋白(Dedicator of cytokinesis, DOCK4、5、7)，上調(diào)收縮基因如a-SMA的表達，繼而促進VSMC收縮并抑制Rac1蛋白活性及遷移能力，使VSMC向分化表型轉(zhuǎn)換。 但Horita等[21]發(fā)現(xiàn)在缺乏血清反應(yīng)因子(Serum Response Factor，SRF)的體外培養(yǎng)VSMC中miR-21的表達增加，細胞的增殖能力及炎性介質(zhì)的表達也隨之增加。還有研究[34]表明miR-21的靶向物磷酸酶張力蛋白同源基因(Phosphatase and Tensin Homolog，PTEN)失活導(dǎo)致VSMC增殖及凋亡減少，而miR-21的主要下游靶向物就是PTEN蛋白，因此在此研究中miR-21的過表達促進了VSMC退分化并增殖。結(jié)合以上兩個實驗，認為miR-21保持于某一水平可促進VSMC分化成熟，并抑制其增殖及遷移，而當(dāng)某些刺激使其過表達后，則會使VSMC退分化，增加其增殖及遷移能力。

Leeper等[35]觀察兩種腹主動脈瘤形成小鼠時發(fā)現(xiàn)，當(dāng)miR-26a表達下降時，VSMC會更多的由未分化型向分化型轉(zhuǎn)換，即抑制miR-26a會加速VSMC分化，抑制VSMC增殖及遷移；而過表達miR-26a則會減弱這種分化及抑制功能。這是由于miR-26a能靶向作用于信號傳導(dǎo)分子-1(SMAD-1)與信號傳導(dǎo)分子-4(SMAD-4)，當(dāng)miR-26a被抑制時，SMAD-1和 SMAD-4基因表達增加，同時改變TGF-β信號，使VSMC向分化型轉(zhuǎn)換。但miR-26a過表達則會抑制SMAD-1，影響VSMC分化。

Grundmann等[36]發(fā)現(xiàn)，miR-100可通過抑制雷帕霉素靶蛋白(Mammalian Target of Rapamycin,mTOR)信號通路調(diào)控細胞增殖、血管形成、內(nèi)皮細胞生長活性及VSMC遷移，過表達miR-100能抑制mTOR表達，抑制細胞增生；但拮抗miR-100或過表達mTOR則可以逆轉(zhuǎn)被miR-100抑制的細胞增殖能力。表明過表達miR-100具有抗血管生成及抗動脈粥樣硬化作用。

miR-365在多種細胞的增殖、凋亡及分化調(diào)控中也具有重要作用。Zhang等[37]通過化學(xué)合成方法使原代大鼠主動脈VSMC的miR-365過表達，經(jīng)過48h培養(yǎng)后，過表達miR-365的VSMC較正常VSMC的細胞數(shù)減少了40%，而72h后這一差別達到了60%；同時發(fā)現(xiàn)過表達miR-365的VSMC中溴-脫氧尿嘧啶摻入法表現(xiàn)為陽性的細胞減少了58%。說明miR-365可明顯抑制VSMC增殖。后續(xù)研究表明，這種作用由miR-365靶向作用于細胞周期蛋白D1(Cyclin D1)，使其不能在mRNA及蛋白水平表達，進而將抑制VSMC增殖所致。

4 小結(jié)與展望

miRNAs作為廣泛存在并具有重要調(diào)控作用的內(nèi)源性微小RNA，通過抑制表達或降解其靶向作用物的mRNA或蛋白質(zhì)轉(zhuǎn)錄而發(fā)揮作用。近年來研究表明miRNAs在VSMC表型轉(zhuǎn)化和各類增殖性疾病的發(fā)展中扮演著重要角色，miR-24、miR-31、miR-221、miR-146a、miR-208可通過促進VSMC增殖來誘導(dǎo)VSMC向未分化表型轉(zhuǎn)換；miR-1、miR-21、miR-26a、miR-100、miR-133、miR-365則可通過抑制VSMC增殖和遷移，上調(diào)收縮基因以及加速VSMC分化來誘導(dǎo)VSMC向分化表型轉(zhuǎn)換。說明體內(nèi)的miRNAs可能成為不同細胞群之間的分泌物介質(zhì)及各種生長因子的信號通路的調(diào)控點。因此，更進一步探討并驗證miRNAs的直接靶標(biāo)基因、miRNAs間的相互作用及信號通路，有助于從新的視角認識動脈粥樣硬化、肺動脈高壓、血管成形術(shù)后再狹窄等因VSMC異常增殖導(dǎo)致的血管疾病，為其發(fā)病機制的研究找到新的切入點，也為研發(fā)新的治療藥物開拓新的思路。

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本文第一作者簡介：

吳 昊(1987-)，男，漢族，碩士研究生，主要研究中西醫(yī)結(jié)合周圍血管病

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The Roles of Micro-RNAs in the Modulation of the Vascular Smooth Muscle Cell Phenotype

WU Hao, ZHOU Tian, DENG Qiao-li ,HU Jia-cai*

Departent of Traditional Chinese Medicine, Renmin Hospital of Wuhan University, Wuhan 430060，China；*

The functions of vascular smooth muscle cells(VSMC), as the main constituent of media in artery, are closely related to the modulation of the VSMC. The proliferation and migration function from the dedifferentiated VSMC phenotype is the pathological basis of cardiovascular and peripheral vascular disease. The differentiated VSMC phenotype is essential to maintain vessel elasticity and contractile function. Many miRNAs play as important regulators in pathological and physiological changes through pathways which are related to the modulation of the VSMC. This article will summarize recent advances of miRNA relating to phenotypic modulation of VSMC.

MicroRNAS；Vascular smooth muscle cell；Phenotype

武漢大學(xué)人民醫(yī)院中醫(yī)科，武漢 430060；*

，E-mail:hujiacai@sohu.com

本文2017-02-22收到，2017-03-24修回

R329.2

A

1005-1740(2017)02-0076-05