段婷婷(綜述) 韓曉杰 龐 雨 徐玉東 王 宇 楊永清 尹磊淼(審校)

(上海中醫(yī)藥大學(xué)上海市針灸經(jīng)絡(luò)研究所 上海 201203)

肌細(xì)胞特異性microRNAs對收縮舒張生物學(xué)效應(yīng)調(diào)控機制的研究進(jìn)展

段婷婷(綜述) 韓曉杰 龐 雨 徐玉東 王 宇 楊永清 尹磊淼△(審校)

(上海中醫(yī)藥大學(xué)上海市針灸經(jīng)絡(luò)研究所 上海 201203)

肌細(xì)胞特異性microRNAs (muscle-specific microRNAs,myomiRs)是一類特異性表達(dá)在肌組織中的內(nèi)源性非編碼小分子RNA,通過轉(zhuǎn)錄后水平負(fù)調(diào)控相關(guān)基因的表達(dá),廣泛參與到一系列生物學(xué)過程中,影響疾病的發(fā)生發(fā)展。肌細(xì)胞相關(guān)疾病(如慢性阻塞性肺炎、肥厚型心肌病等)的發(fā)生、發(fā)展可引起myomiRs及其下游靶基因表達(dá)改變,從而進(jìn)一步影響疾病的發(fā)展、預(yù)后及轉(zhuǎn)歸。本文將綜述miR-1、miR-133、miR-206、miR-208和miR-499等常見myomiRs在橫紋肌和非橫紋肌收縮舒張機制中的作用,重點關(guān)注myomiRs對肌細(xì)胞收縮舒張生物學(xué)效應(yīng)的影響,以期為肌細(xì)胞相關(guān)疾病治療提供新思路。

肌細(xì)胞特異性microRNAs; 平滑肌; 骨骼肌; 心肌; 肌肉收縮舒張機制

microRNAs (miRNAs)是含20～22個核苷酸的非編碼小分子RNA,通過轉(zhuǎn)錄后水平負(fù)調(diào)控相關(guān)基因的表達(dá)。MiRNAs分布具有組織特異性,其中肌細(xì)胞特異性miRNAs (muscle-specific microRNAs,myomiRs)[1]僅表達(dá)在肌組織包括平滑肌、心肌、骨骼肌中[2],只針對肌細(xì)胞相關(guān)基因進(jìn)行轉(zhuǎn)錄后表達(dá)調(diào)控,并顯著影響肌細(xì)胞收縮舒張、增殖和分化[3]。目前常見的myomiRs包括miR-1、miR-133、miR-206、miR-208及miR-499等[4]。myomiRs可影響肌細(xì)胞收縮舒張、增殖及分化等重要生物學(xué)功能,在轉(zhuǎn)錄后水平負(fù)性調(diào)控相應(yīng)靶基因表達(dá),并和相關(guān)轉(zhuǎn)錄因子、信號蛋白、激酶等相互作用形成復(fù)雜的生物調(diào)控網(wǎng)絡(luò)[3,5]。myomiRs在肌細(xì)胞收縮舒張生物學(xué)效應(yīng)中扮演重要角色,如myomiRs參與調(diào)節(jié)蘭尼堿受體(ryanodine,RyR)、1,4,5-三磷酸肌醇受體(inositol 1,4,5-triphosphate

receptor,IP3R)控制鈣離子釋放,從而影響肌細(xì)胞收縮[6-7]。

慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)、肥厚型心肌病(hypertrophic cardiomyopathy,HCM)等肌細(xì)胞相關(guān)疾病可引起myomiRs表達(dá)改變,影響下游靶基因表達(dá),誘發(fā)肌細(xì)胞的過度收縮、增殖,最終影響到疾病的發(fā)展[8-11](表1)。闡明myomiRs參與肌細(xì)胞收縮舒張過程的生物學(xué)機制,將為平滑肌收縮舒張功能障礙相關(guān)疾病提供新的治療策略和思路。

鑒于肌球蛋白輕鏈(myosin light chain,MLC)在肌細(xì)胞收縮舒張過程中所起關(guān)鍵調(diào)控作用,學(xué)界將肌肉收縮舒張分為MLC磷酸化依賴性途徑和非MLC磷酸化依賴性途徑[12-13]。本文將從myomiRs對非橫紋肌(平滑肌)和橫紋肌(心肌與骨骼肌)的收縮舒張效應(yīng)進(jìn)行綜述。

表1 myomiRs表達(dá)與肌細(xì)胞相關(guān)疾病

COPD:Chronic obstructive pulmonary disease.

平滑肌收縮舒張機制及myomiRs對其影響 MLC在平滑肌細(xì)胞收縮舒張過程中起重要作用,據(jù)此可將收縮舒張機制分為MLC磷酸化依賴性途徑(包括Ca2+-CaM-MLCK機制和Rho-ROK-MLCP、PKC-CPI-17-MLCP機制)及非MLC磷酸化依賴性途徑(細(xì)肌絲相關(guān)蛋白的調(diào)節(jié)機制)[12-13,16]。

MyomiRs在MLC磷酸化依賴性收縮的作用MLC磷酸化水平是決定平滑肌收縮程度的一個重要因素,其磷酸化水平受到Ca2+/鈣調(diào)蛋白(calmodulin,CaM)依賴的肌球蛋白輕鏈激酶(myosin light chain kinase,MLCK)和非Ca2+依賴的肌球蛋白磷酸酶(myosin light chain phosphatase,MLCP)的雙重調(diào)節(jié)[17]。MLCK磷酸化MLC促進(jìn)肌球蛋白單體形成肌絲,收縮平滑肌細(xì)胞;MLCP脫磷酸化肌球蛋白舒張平滑肌細(xì)胞。平滑肌細(xì)胞舒縮狀態(tài)取決于MLC的磷酸化程度,由MLCK/MLCP比值大小直接決定,并受胞質(zhì)內(nèi)鈣離子濃度、Rho激酶和鈣調(diào)蛋白等因素調(diào)控[17-18]。

MyomiRs參與 Ca2+-CaM-MLCK機制 該機制也可被稱作為鈣依賴機制[19]。當(dāng)平滑肌細(xì)胞受到外界刺激時,膜成分磷脂酰肌醇4,5二磷酸(phosphatidylinositol 4,5-bisphosphate,PIP2)在磷脂酶C (phospholipase C,PLC)的作用下分解為三磷酸肌醇(inositol 1,4,5-trisphosphate,IP3)和二酰甘油(diacylglycerol,DAG),前者激活肌漿網(wǎng)使內(nèi)鈣釋放,后者通過L型鈣通道開放,引起鈣離子內(nèi)流,進(jìn)一步激活肌漿網(wǎng)上的蘭尼堿受體,促進(jìn)內(nèi)鈣釋放。這種“外鈣內(nèi)流和內(nèi)鈣釋放”方式使胞質(zhì)內(nèi)的Ca2+濃度升高[16],Ca2+/CaM復(fù)合體形成進(jìn)而激活MLCK,磷酸化MLC第19位絲氨酸,收縮平滑肌細(xì)胞[20]。當(dāng)Ca2+濃度下降至10-7mmol/L時[21],CaM與MLCK分離,MLCK活性消失,此時MLCP作用占主導(dǎo)地位,MLCP降低MLC磷酸化程度,從而舒張平滑肌細(xì)胞(圖1)。

GPCR:G protein coupled receptor;PLC:Phospholipase C;PIP2:Phosphatidylinositol 4,5-bisphosphate;IP3:Inositol 1,4,5-trisphosphate;DAG:Diacylglycerol;IP3R:Inositol 1,4,5-trisphosphate receptor;RyR:Ryanodine receptors;SR:Sarcoplasmic reticulum;CaM:Calmodulin;MLCK:Myosin light chain kinase;MLC:Myosin light chain;PKC:Protein kinase C;LTCC:L-type calcium channel;CaMKⅡ:Calmodulin kinase type Ⅱ.

圖1 鈣依賴性收縮機制通路圖

Fig 1 Pathway of calcium dependent muscle contraction mechanism

研究發(fā)現(xiàn)miR-1通過抑制α-平滑肌肌動蛋白(α-smooth muscle actin)和平滑肌22蛋白(smooth muscle-22,SM22)表達(dá),減少肌動蛋白細(xì)胞骨架形成,從而抑制心肌素誘導(dǎo)的血管平滑肌收縮[22]。miR-145下調(diào)鈣調(diào)蛋白激酶Ⅱ (calmodulin kinase type Ⅱ,CaMKⅡ)增加L型鈣通道(L-type calcium channel,LTCC)表達(dá),胞外Ca2+內(nèi)流增多,誘發(fā)SR釋放出更多Ca2+,胞質(zhì)內(nèi)Ca2+總濃度上升,間接促進(jìn)血管平滑肌的收縮[23]。目前雖未找到相關(guān)myomiRs能夠直接作用MLCK的文獻(xiàn),但有研究表明在內(nèi)皮細(xì)胞中,miR-155能夠直接作用RhoA和MLCK,抑制其表達(dá),使p-MLC表達(dá)減少,抑制細(xì)胞的收縮及應(yīng)力纖維的形成[24]。

MyomiRs參與Rho-ROK-MLCP與PKC-CPI-17-MLCP機制 該機制又被稱為鈣敏化機制,主要是指對MLCP的抑制作用,增強了MLC磷酸化促使平滑肌進(jìn)一步收縮[25]。鈣敏化機制主要通過Rho-ROK通路和PKC-CPI-17通路抑制MLCP活性。Rho-ROK通路使肌球蛋白靶亞基(myosin phosphatase target subunit,MYPT1)上T853和T696位點磷酸化,直接導(dǎo)致MLCP失活[26-27]。而PKC磷酸化蛋白激酶C抑制蛋白(C kinase-potentiated phosphatase inhibitor of 17 kD,CPI-17)與MLCP催化亞基緊密結(jié)合,間接使MLCP失活[12,28](圖2)。

GPCR:G protein coupled receptor;GEF:Guanine nucleotide exchange factors;ROK:Rho-associated kinase;MLCP:Myosin light chain phosphatase;MLC:Myosin light chain;DAG:Diacylglycerol;PKC:Protein kinase C;CPI-17:Protein kinase-potentiated phosphatase inhibitor of 17 kD.

圖2 鈣敏化收縮機制通路圖

Fig 2 Pathway of calcium sensitization contraction mechanism

研究發(fā)現(xiàn)氣道平滑肌中RhoA表達(dá)受到miR-133a負(fù)調(diào)控[29]。給予氣管平滑肌細(xì)胞IL-13,發(fā)現(xiàn)在干預(yù)后第3、6小時miR-133a的表達(dá)顯著降低,RhoA表達(dá)增多,氣管平滑肌收縮[30]。糖尿病和高血脂介導(dǎo)的炎性反應(yīng)能夠通過下調(diào)miR-206和其他一些非myomiRs表達(dá),如miR-10a、miR-139b,增加ROK和連接蛋白的表達(dá),從而誘導(dǎo)血管平滑肌細(xì)胞收縮和血管高反應(yīng)性[31]。

MyomiRs在非MLC磷酸化依賴性收縮的作用

MyomiRs參與細(xì)肌絲相關(guān)蛋白機制 在平滑肌的收縮舒張過程中除了粗肌絲的調(diào)節(jié)外,細(xì)肌絲也可調(diào)節(jié)其收縮舒張[32]。鈣調(diào)結(jié)合蛋白(caldesmon,CaD)和原肌球蛋白(tropomyosin,TM)是參與細(xì)肌絲相關(guān)調(diào)節(jié)的重要蛋白,靜息狀態(tài)下,二者能夠分別抑制actin-myosin的結(jié)合和myosin ATP酶的活性,此時肌肉處于舒張狀態(tài)[33]。在收縮信號的刺激下,CaD、TM和HSP27被磷酸化,磷酸化CaD構(gòu)象改變與actin-TM解離,磷酸化HSP27與磷酸化TM結(jié)合在actin上滑動,暴露出myosin結(jié)合位點。actin與myosin結(jié)合,引發(fā)收縮[34]。

研究發(fā)現(xiàn)在血管平滑肌細(xì)胞中,miR-143和miR-145高表達(dá)能夠通過下調(diào)枯否樣因子(krupple-like factor,KLF)4和KLF5,增加鈣調(diào)理蛋白(calponin,CaP)、平滑肌細(xì)胞肌球蛋白重鏈(smooth muscle myosin heavy chain,SM-MHC)等收縮蛋白的表達(dá)[35]。干擾素β和γ能夠同時提高miR-143、145和氣道平滑肌中α肌動蛋白表達(dá)量,這可能和氣管平滑肌收縮相關(guān)[36]。

臨床疾病 MyomiRs通過調(diào)控下游靶基因,參與哮喘、動脈粥樣硬化、肺動脈高壓等疾病。miR-133是氣管平滑肌高反應(yīng)性的重要調(diào)節(jié)者。小鼠過敏性哮喘模型氣道高反應(yīng)性顯著增高并伴有IL-13、RhoA蛋白表達(dá)增強和miR-133a降低[30]。進(jìn)一步研究發(fā)現(xiàn),IL-13通過降低miR-133a表達(dá),增高RhoA,從而誘發(fā)氣道平滑肌收縮增強并出現(xiàn)氣道高反應(yīng)性[29]。

miR-145在動脈粥樣硬化和肺動脈高壓的形成中也發(fā)揮著關(guān)鍵作用。臨床研究發(fā)現(xiàn)在動脈粥樣硬化血管壁上miR-145表達(dá)較正常組顯著降低[37]。而血管平滑肌細(xì)胞表型轉(zhuǎn)換作為動脈粥樣硬化的起始過程,受到miR-145負(fù)調(diào)節(jié),即miR-145降低會促進(jìn)血管平滑肌細(xì)胞分化,從而加快動脈粥樣硬化病變的進(jìn)程[38]。在肺動脈高壓的形成中,miR-145等myomiRs也可通過調(diào)控血管細(xì)胞的收縮增殖、凋亡可誘發(fā)肺動脈管壁壓力升高[39]。

橫紋肌收縮舒張機制及myomiRs對其調(diào)控 根據(jù)MLC在橫紋肌中收縮和舒張中所起的作用,將橫紋肌的收縮舒張機制也可按照MLC磷酸化依賴性途徑(Ca2+-CaM-MLCK機制)和非MLC磷酸化依賴性途徑,包括Ca2+-TN-TM機制和肌球蛋白重鏈(myosin heavy chain,MHC)調(diào)節(jié)機制。

MyomiRs在MLC磷酸化依賴性收縮的作用

MyomiRs參與調(diào)控Ca2+-CaM-MLCK機制 類似于平滑肌,橫紋肌胞內(nèi)Ca2+增高能夠激活CaM,Ca2+-CaM復(fù)合體繼而激活MLCK,從而引起MLC磷酸化[40-41]。MLC磷酸化能夠傾斜、旋轉(zhuǎn)橫橋,促進(jìn)actin與myosin結(jié)合,收縮平滑肌[42]。胞內(nèi)鈣離子的升高激活CaM,Ca2+-CaM復(fù)合體激活MLCK,MLCK磷酸化MLC,促進(jìn)橫橋與actin結(jié)合,從而促進(jìn)收縮。

研究發(fā)現(xiàn)高表達(dá)的miR-1能夠通過調(diào)節(jié)亞基B56α,抑制蛋白磷酸酶2A (protein phosphatase 2A,PP2A)生物學(xué)功能,激活RyR2,促使肌質(zhì)網(wǎng)上自發(fā)的鈣離子釋放,提高胞內(nèi)鈣離子濃度引起細(xì)胞收縮。在壓力負(fù)荷和神經(jīng)激素刺激下,miR-133a下調(diào)使IP3RⅡ表達(dá)增多,增加促肥厚鈣信號(IP3-induced calcium release,IICR)形成和心肌病理性重構(gòu),使得代償性心肌總量增加、心肌收縮力加強[43]。miR-1能通過對鈣依賴信號分子CaM、肌細(xì)胞強化因子2a (myocyte enhancer factor-2a,Mef2a)、轉(zhuǎn)錄因子GATA4負(fù)調(diào)控,使得代償性心肌總量減弱、心肌收縮力減弱,減弱小鼠心肌肥厚發(fā)生[44]。

MyomiRs在非MLC磷酸化依賴性收縮的作用

Ca2+-TN-TM機制 橫紋肌不同于平滑肌,誘發(fā)肌肉收縮的是Ca2+與肌鈣蛋白(troponin,TN)結(jié)合[42]。當(dāng)肌細(xì)胞興奮而使胞質(zhì)內(nèi)Ca2+增加時,Ca2+便與細(xì)絲上的TN結(jié)合,構(gòu)象發(fā)生變化、牽拉原肌球蛋白滑動移位,暴露結(jié)合位點,actin與myosin結(jié)合,橫橋周期生成,牽拉細(xì)肌絲向粗肌絲內(nèi)滑行,肌節(jié)縮短,出現(xiàn)肌肉收縮。

MyomiRs參與MHC調(diào)節(jié)機制 MHC是心肌細(xì)胞控制收縮性能的主要決定因素[45]。α-MHC和β-MHC的表達(dá)比可影響心肌肌小節(jié)的收縮[46]。用丙基硫氧嘧啶處理雄性鼠使之心肌MHC產(chǎn)生α-MHC并向β-MHC轉(zhuǎn)換,發(fā)現(xiàn)α-MHC表達(dá)減少伴隨著橫橋周期速率減少,與橫橋周期動力學(xué)之間存在線性關(guān)系[47](圖3)。

研究發(fā)現(xiàn)當(dāng)機體處于應(yīng)激或者甲狀腺功能減退時,能誘導(dǎo)成人心肌α-MHC向β-MHC轉(zhuǎn)換[48],橫橋再生速率減緩,從而出現(xiàn)收縮效率減退[49]。miR-208a通過抑制甲狀腺受體相關(guān)蛋白(thyroid receptor-associated protein 1,THRAP1)抑制β-MHC表達(dá)。依賴miR-208α,miR-208b和miR-499能控制肌球蛋白表達(dá)量,肌纖維種類和性能[50],從而調(diào)控收縮。

GPCR:G protein coupled receptor;PLC:Phospholipase C;PIP2:Phosphatidylinositol 4,5-bisphosphate;IP3:Inositol 1,4,5-trisphosphate;DAG:Diacylglycerol;SR:Sarcoplasmic reticulum;CaM:Calmodulin;MLCK:Myosin light chain kinase;MLC:Myosin light chain;PP2A:Protein phosphatase 2A;MHC:Myosin heavy chain.

圖3 橫紋肌收縮調(diào)節(jié)機制通路圖

Fig 3 Pathways of strained muscle contraction regulation

臨床疾病 大量研究表明myomiRs與心衰及HCM緊密相關(guān)。對心衰患者使用醛固酮受體拮抗劑(依普利酮)能夠有效抑制miR-208a表達(dá),提高THRAP1,從而抑制心肌病理性肥厚[51]。機制研究表明miR-208a通過抑制THRAP1降低α-MHC、上調(diào)β-MHC表達(dá)發(fā)揮誘導(dǎo)心衰作用[14]。而MHC組成的微小改變對心肌收縮具有一定作用,如用β-MHC替換掉12%的α-MHC,心肌纖維ATP酶活性下降23%,收縮力下降15%[52]。HCM發(fā)病過程中,miR-1和miR-133可負(fù)調(diào)控Ca2+及CaM、Mef2a等信號蛋白,增加肌總量和肌收縮力[53]。

MyomiRs在心肌梗死中起到預(yù)測和監(jiān)控作用。研究發(fā)現(xiàn)急性心?；颊哐錷iR-1、miR-208a和miR-499表達(dá)量顯著升高,分別為正常組300、2000和250倍[54]。進(jìn)一步分析顯示上述三者均可作為預(yù)測心肌梗死生物學(xué)標(biāo)記,而miR-208a和miR-499預(yù)測效果優(yōu)于miR-1(特異性和敏感性約高10%)[55]。在對ST段抬高心?；颊哳A(yù)測中,miR-208b敏感性和特異性均高達(dá)100%[56]。

結(jié)語 MyomiRs生物學(xué)功能多樣,可通過作用相應(yīng)下游靶基因發(fā)揮不同作用。myomiRs表達(dá)失調(diào)與肌細(xì)胞疾病發(fā)生發(fā)展密切相關(guān)。在肌細(xì)胞相關(guān)疾病中,myomiRs改變可調(diào)節(jié)肌細(xì)胞收縮舒張機制生物網(wǎng)絡(luò)中的轉(zhuǎn)錄因子、信號蛋白、激酶等表達(dá),改變肌細(xì)胞舒縮功能,最終影響疾病預(yù)后與轉(zhuǎn)歸。

臨床應(yīng)用上,目前myomiRs主要用于診斷肌細(xì)胞相關(guān)性疾病,如miR-499等可作為新一代心肌梗死生物標(biāo)志物。治療方面,myomiRs表現(xiàn)出強勁的潛力:哮喘患者可通過特異性增高氣管平滑肌細(xì)胞miR-133a表達(dá),舒張氣道平滑肌、緩解哮喘氣道高反應(yīng)性;提高miR-206表達(dá),可以舒張血管平滑肌、降低高血脂誘發(fā)的血管高反應(yīng)性,達(dá)到保護(hù)心血管的作用[34]。在心衰患者治療中,可通過慢病毒給藥、使用醛固酮受體抑制劑等方式降低miR-208a表達(dá),有效抑制心肌病理性修復(fù),提高心衰患者存活率。提高心衰患者血清miR-133和miR-1表達(dá),抑制肌纖維量和肌收縮力,減緩心肌肥厚,從而保護(hù)心臟。因此,進(jìn)一步探索和研究myomiRs對肌肉收縮舒張機制的影響,發(fā)展myomiRs相關(guān)替代療法,將為肌細(xì)胞相關(guān)疾病提供新的治療方案。

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Progress in the biological effects of muscle-specific microRNAs on muscle contraction and relaxation

DUAN Ting-ting, HAN Xiao-jie, PANG Yu, XU Yu-dong, WANG Yu, YANG Yong-qing, YIN Lei-miao△

(ShanghaiResearchInstituteofAcupunctureandMeridian,ShanghaiUniversityofTraditionalChineseMedicine,Shanghai201203,China)

Muscle-specific microRNAs (myomiRs) are a class of small endogenous non-coding RNAs that expressed specifically in the muscle tissue.By negatively regulating related gene expression at post-translational level,they participate in a variety of biological processes and affects the occurrence and development of diseases.The occurrence and development of muscle-related diseases,such as chronic obstructive pneumonia disease,hypertrophic cardiomyopathy and so on,induce the expression changes of myomiRs and downstream target genes.The effects of myomiRs on the muscle contraction will affect the development of the disease.This paper will review the biological effects of common myomiRs,such as miR-1,miR-133,miR-206,miR-208 and miR-499 in muscle contraction and relaxation,including striated and non-striated muscle.Better understanding of the effects of myomiRs on the biological effects of muscle contraction and relaxation will provide a new idea for the treatment of muscle-related diseases.

muscle-specific microRNAs; smooth muscle; skeletal muscle; cardiac muscle;mechanism of muscle contraction and relaxation

國家自然科學(xué)基金( 81473760,81574058);上海市人才發(fā)展基金(201610);上海市衛(wèi)生系統(tǒng)優(yōu)秀青年人才培養(yǎng)計劃( XYQ2013081);上海市中醫(yī)藥事業(yè)發(fā)展三年行動計劃重大研究項目(ZY3-CCCX-3-3005)

R34

B

10.3969/j.issn.1672-8467.2017.03.023

2016-09-01;編輯:張秀峰)

△Corresponding author E-mail:collegeylm@shutcm.edu.cn

*This work was supported by the National Natural Science Foundation of China (81473760,81574058),Shanghai Talent Development Fund (201610),Training Plan for the Excellent Youth Scholars of Shanghai Health System (XYQ2013081) and the Three-year Action Plan for Development of Chinese Traditional Medicine in Shanghai (ZY3-CCCX-3-3005).