組蛋白去乙酰化酶在調(diào)節(jié)心肌肥大過(guò)程中的作用機(jī)制

任戀，吳秀山，李永青

綜 述

組蛋白去乙?；冈谡{(diào)節(jié)心肌肥大過(guò)程中的作用機(jī)制

任戀，吳秀山，李永青

湖南師范大學(xué)省部共建淡水魚(yú)類(lèi)發(fā)育生物學(xué)國(guó)家重點(diǎn)實(shí)驗(yàn)室，教育部重點(diǎn)實(shí)驗(yàn)室，生命科學(xué)學(xué)院心臟發(fā)育研究中心，長(zhǎng)沙 410081

心肌肥大(cardiac hypertrophy)是由外周組織對(duì)血流動(dòng)力學(xué)需求增加而發(fā)生的一種代償性反應(yīng)。在心肌肥大過(guò)程中，不同時(shí)期的不同類(lèi)型的基因表達(dá)受到生理和病理信號(hào)的多級(jí)轉(zhuǎn)錄調(diào)控。組蛋白乙?；鳛樽顝V泛的翻譯后修飾方式，受相互拮抗的組蛋白乙?；?histone acetyltransferases, HAT)和組蛋白去乙?；?histone deacetylases，HDACs)的精細(xì)控制。近年來(lái)研究表明，HDACs作為一類(lèi)抑制轉(zhuǎn)錄過(guò)程并含有高度保守的脫乙酰酶結(jié)構(gòu)域家族酶，通過(guò)多種作用途徑調(diào)控心肌肥大過(guò)程中的基因表達(dá)。本文主要綜述了組蛋白去乙?；刚{(diào)節(jié)心肌肥大過(guò)程的相關(guān)研究進(jìn)展，通過(guò)闡明不同種類(lèi)HDACs在心肌肥大中的作用和分子機(jī)制，為不同類(lèi)型心肌肥大和心衰的發(fā)病治療提供新的思路，為新藥設(shè)計(jì)提供分子靶點(diǎn)。

心肌肥大；轉(zhuǎn)錄調(diào)控；翻譯后修飾；組蛋白去乙?；?；分子機(jī)制

心臟組織對(duì)生理和病理刺激的持續(xù)反應(yīng)會(huì)導(dǎo)致心臟細(xì)胞尺寸增大，被稱(chēng)為心肌肥大(cardiac hyper-trophy)，是由外周組織對(duì)血流動(dòng)力學(xué)需求增加而發(fā)生的一種代償性反應(yīng)。早期心肌肥大會(huì)出現(xiàn)心肌細(xì)胞的細(xì)胞負(fù)荷增加和胎兒基因的重編程等表征。心肌肥大初期可通過(guò)增厚心臟壁以應(yīng)對(duì)高血壓、心臟損傷、瓣膜疾病和心肌梗塞引起的壓力增加，具有一定生理性的代償意義，但持續(xù)的肥大會(huì)使心臟功能下降進(jìn)入病理狀態(tài)[1]，從而導(dǎo)致心肌病、纖維化和心力衰竭等病理表型。

在心肌肥大過(guò)程中，不同時(shí)期和不同類(lèi)型的基因表達(dá)受到生理和病理信號(hào)的多級(jí)轉(zhuǎn)錄調(diào)控。組蛋白乙?；鳛樽顝V泛的翻譯后修飾方式，受相互拮抗的組蛋白乙?；?histone acetyltransferase, HAT)和組蛋白去乙酰化酶(histone deacetylases, HDACs)的精細(xì)控制，其狀態(tài)的改變將導(dǎo)致染色體結(jié)構(gòu)發(fā)生變化從而影響相關(guān)基因的轉(zhuǎn)錄。目前研究表明，HDACs既可以通過(guò)緊縮染色質(zhì)而抑制基因的轉(zhuǎn)錄，也可以通過(guò)調(diào)控轉(zhuǎn)錄因子活性或酶活性來(lái)調(diào)控基因的轉(zhuǎn)錄[2]。本文介紹了HDACs的分子結(jié)構(gòu)特點(diǎn)，著重對(duì)不同種類(lèi)HDACs在心肌肥大中的作用和分子機(jī)制進(jìn)行綜述，并概述了HDACs抑制劑的抗心肌肥大作用，以期為不同類(lèi)型心肌肥大和心衰的發(fā)病治療提供新的思路，為新藥設(shè)計(jì)提供分子靶點(diǎn)。

1 HDACs的分子結(jié)構(gòu)特點(diǎn)

HDACs家族是一類(lèi)抑制轉(zhuǎn)錄過(guò)程并含有高度保守的脫乙酰酶結(jié)構(gòu)域家族酶總稱(chēng)。哺乳動(dòng)物HDACs家族酶的18個(gè)成員被分為I類(lèi)、IIa類(lèi)、IIb類(lèi)、III類(lèi)和IV類(lèi)，具有不同的結(jié)構(gòu)、酶功能、亞細(xì)胞定位和表達(dá)模式以及生物學(xué)作用[3~7]。I、II和IV類(lèi)HDACs是鋅(Zn2+)依賴性酶，彼此之間呈現(xiàn)序列相似性，但與III類(lèi)HDACs沒(méi)有同源性，后者需要NAD+進(jìn)行脫乙?；饔谩Ｆ駷橹梗渌?類(lèi)HDACs都有成員被發(fā)現(xiàn)參與心肌肥大的調(diào)節(jié)，只有IV類(lèi)HDAC即HDAC11尚無(wú)相關(guān)報(bào)道。相關(guān)內(nèi)容總結(jié)見(jiàn)表1和圖1。

2 I類(lèi)HDACs在心肌肥大中的作用

HDAC2敲除小鼠（Mus musculus）或轉(zhuǎn)基因小鼠以及心肌細(xì)胞中的研究結(jié)果都已表明，I類(lèi)HDAC中的 HDAC2對(duì)心臟肥大具有正調(diào)控作用[13~16]。HDAC2敲除小鼠出生后24 h內(nèi)死于嚴(yán)重心臟畸形，心肌細(xì)胞由于過(guò)度增殖導(dǎo)致右心室腔閉塞，并出現(xiàn)心動(dòng)過(guò)緩的現(xiàn)象[13]。HDAC2在調(diào)節(jié)心肌肥大基因轉(zhuǎn)錄過(guò)程中起著非常重要的作用[17]，相關(guān)機(jī)制主要集中在兩方面：一方面是HDAC2直接作用于抗肥大調(diào)節(jié)因子，通過(guò)下調(diào)抗肥大調(diào)節(jié)因子表達(dá)而促進(jìn)心肌肥大。活化的HDAC2被募集到驅(qū)動(dòng)抗肥大調(diào)節(jié)因子(如INPP5F或KLF4)的啟動(dòng)子上，通過(guò)對(duì)抗肥大調(diào)節(jié)因子啟動(dòng)子處的組蛋白去乙酰化，下調(diào)抗肥大調(diào)節(jié)因子的表達(dá)，繼而導(dǎo)致被其阻遏的胎兒基因程序的再激活，引起心肌肥大現(xiàn)象[14]。其中HDAC2下調(diào)抗肥大調(diào)節(jié)因子INPP5F的表達(dá)后，通過(guò)Pdk- Akt-Gsk3β信號(hào)通路減輕了Gsk3β對(duì)elF2b、c-Myc、GATA4和β-catenin等促肥大因子的抑制而引起心肌肥大[15]。HOPx/HDAC2/HSP70信號(hào)下調(diào)抗肥大轉(zhuǎn)錄因子KLF4的表達(dá)，下調(diào)的KLF4轉(zhuǎn)錄因子能提高肥大靶標(biāo)基因心房利鈉肽前體表達(dá)水平從而引起心肌肥大[16]。HDAC2抗心肌肥大的另一個(gè)作用機(jī)制是可直接作用于轉(zhuǎn)錄因子，通過(guò)調(diào)節(jié)轉(zhuǎn)錄因子的活性來(lái)調(diào)控心肌細(xì)胞增殖和肥大靶基因的表達(dá)。在心肌細(xì)胞中，轉(zhuǎn)錄因子SRF驅(qū)動(dòng)肥大靶基因表達(dá)，SRF的活性和組蛋白翻譯后p300乙酰修飾化存在強(qiáng)烈的相關(guān)性[51]。SRF的輔因子Myocardin募集p300，誘導(dǎo)組蛋白3乙?；鰪?qiáng)SRF轉(zhuǎn)錄因子的活性，促進(jìn)肥大靶基因表達(dá)[52]。心肌細(xì)胞中特異表達(dá)的Hopx蛋白可以通過(guò)招募HDAC2形成轉(zhuǎn)錄抑制復(fù)合物抑制心肌細(xì)胞中SRF轉(zhuǎn)錄因子活性來(lái)抑制肥大靶基因的表達(dá)[18]。另外，Hopx還可增加HDAC2-GATA4復(fù)合物的穩(wěn)定性，導(dǎo)致轉(zhuǎn)錄因子GATA4去乙酰化而抑制該轉(zhuǎn)錄因子與DNA結(jié)合及轉(zhuǎn)錄激活的能力，抑制心肌細(xì)胞增殖[19]。雷帕霉素(mammalian target of rapamycin, mTOR)激酶是包括生理性和病理性心臟肥大在內(nèi)的多種狀況下細(xì)胞生長(zhǎng)的核心調(diào)節(jié)因子。藥理和遺傳方法的研究證明，抑制I類(lèi)HDAC通過(guò)抑制mTOR活性而抑制病理性心臟肥大，依賴于結(jié)節(jié)性硬化復(fù)合物2 (tuberous sclerosis complex 2, TSC2)的mTOR抑制是I類(lèi)HDAC抑制劑抑制病理性心肌肥大的關(guān)鍵靶點(diǎn)。HDAC1、2、3對(duì)mTOR和心肌細(xì)胞肥大生長(zhǎng)的調(diào)節(jié)作用存在功能冗余[8]。

表1 HDACs亞族分子結(jié)構(gòu)特點(diǎn)

圖1 HDACs亞族分子在心肌肥大中的作用靶標(biāo)和功能

Fig. 1 Target and function of HDACs subfamily molecules in myocardial hypertrophy

A：I和II類(lèi)HDACs在心肌肥大中的作用靶標(biāo)和功能；B：III類(lèi)HDACs在心肌肥大中的作用靶標(biāo)和功能。

HDAC1敲除小鼠胚胎由于嚴(yán)重的增殖缺陷和發(fā)育延遲在E10.5之前就會(huì)死亡，HDAC1的缺失會(huì)誘導(dǎo)HDAC2和HDAC3的表達(dá)，但并不能彌補(bǔ)HDAC1的作用[9]。在小鼠心臟中同時(shí)特異性敲除HDAC1和HDAC2等位基因會(huì)導(dǎo)致胚胎致死，并伴有心臟心律失常、擴(kuò)張型心肌病、骨骼肌特定收縮蛋白和心臟中鈣通道相關(guān)基因的表達(dá)上調(diào)，說(shuō)明HDAC1與HDAC2在心臟功能上可能存在冗余，單獨(dú)失活HDAC1或HDAC2 并不能阻斷異丙腎上腺素(isoprenaline, ISO)或者主動(dòng)脈縮窄術(shù)(transverse aortic constriction, TAC)引起的肥大，并且同時(shí)出現(xiàn)在sin3、NuRD、CoREST和PRC2等抑制復(fù)合物中[10]。在高同型半胱氨酸血癥患者中，形成HDAC1和肌細(xì)胞增強(qiáng)因子2C (myocyte enhancer factor-2C, MEF2C)阻遏復(fù)合物，使心肌肥大重要轉(zhuǎn)錄因子MEF2C失活，導(dǎo)致心肌細(xì)胞中的抗肥大miR-133a的表達(dá)下降而誘導(dǎo)心肌肥大[11]。HDAC1還可與HDAC5形成復(fù)合物。HDAC5-HDAC1復(fù)合體使轉(zhuǎn)錄因子Nkx2.5去乙?；欢ヒ阴；腘kx2.5募集p300結(jié)合到Ncx1啟動(dòng)子處上調(diào)Ncx1的表達(dá)，促進(jìn)心肌細(xì)胞中的鈉鈣交換引起心肌肥大[12]。

與其他I類(lèi)HDACs相反，HDAC3對(duì)心肌肥大可能主要起抑制作用。HDAC3是唯一一個(gè)在體外和體內(nèi)使MEF2D去乙?；腎類(lèi)HDAC；它通過(guò)與MEF2的MADS結(jié)構(gòu)域、以及乙?；D(zhuǎn)移酶p300以及p300/CBP結(jié)合因子(p300/CBP-associated factor, PCAF)直接結(jié)合，使MEF2D和PCAF都去乙?；?，從而抑制MEF2依賴性轉(zhuǎn)錄和肌生成[21]。在ISO誘導(dǎo)的肥大心肌中，心肌肥大信號(hào)的重要激酶p38 MAPK是受乙?；せ疃c其磷酸化狀態(tài)無(wú)關(guān)。p300和PCAF使p38的K53和K152發(fā)生賴氨酸乙?；?，提高p38的激酶活性，但HDAC3則使p38去乙?；种破浠钚訹22]。心肌細(xì)胞特異性過(guò)表達(dá)的轉(zhuǎn)基因小鼠的研究結(jié)果也顯示，幼鼠心室心肌尤其是室間隔增厚、心室腔減小，但心肌增厚是由于心肌細(xì)胞增生而非心肌肥大；與轉(zhuǎn)基因小鼠不同，轉(zhuǎn)基因小鼠在3個(gè)月大時(shí)并未出現(xiàn)心肌肥大，也不增加ISO引起的心肌肥大程度[23]。

HDAC8也被證明可調(diào)節(jié)心肌肥大。在醋酸去氧皮質(zhì)酮–鹽誘導(dǎo)高血壓的大鼠模型中，HDACs抑制劑丙戊酸鈉處理使HDAC6和HDAC8的酶活性下降，抑制慢性高血壓大鼠的心肌肥大及纖維化[24]。Yan等[25]研究顯示miR-21-3p抑制TAC和血管緊張素(angiotensin IIAng II)誘導(dǎo)的心肌肥大的作用靶點(diǎn)是沉默HDAC8；HDAC8的表達(dá)通過(guò)提升磷酸化Akt和磷酸化Gsk3β而削弱miR-21-3p介導(dǎo)的心肌肥大抑制作用。Li等[20]研究也表明HDAC8和HDAC2在腎性高血壓大鼠的心臟重塑中起關(guān)鍵作用。有關(guān)I類(lèi)HDACs調(diào)控心肌肥大的相關(guān)作用機(jī)制見(jiàn)圖2。

3 II類(lèi)HDACs在心肌肥大中的作用

IIa類(lèi)HDACs家族的調(diào)控能力主要通過(guò)在細(xì)胞核和細(xì)胞質(zhì)之間穿梭來(lái)實(shí)現(xiàn)[53](圖3)。IIa類(lèi)HDACs家族具有較長(zhǎng)的N-末端延伸，能夠結(jié)合轉(zhuǎn)錄因子MEF2和伴侶蛋白14-3-3產(chǎn)生HDACs信號(hào)響應(yīng)。IIa類(lèi)HDACs家族成員被鈣/鈣調(diào)蛋白依賴性蛋白激酶(CaMK)或蛋白激酶D(PKD)等激酶磷酸化后與伴侶蛋白14-3-3結(jié)合，使IIa類(lèi)HDACs與MEF2解聚，從細(xì)胞核穿梭至細(xì)胞質(zhì)[54,55]。HAT p300則與游離的MEF2上的HDACs結(jié)合位點(diǎn)相結(jié)合，將MEF2從轉(zhuǎn)錄抑制狀態(tài)轉(zhuǎn)化為激活狀態(tài)[56]?；罨腗EF2轉(zhuǎn)錄因子通過(guò)直接促進(jìn)肥大靶基因表達(dá)或與其他相關(guān)促肥大轉(zhuǎn)錄因子(如GATA和NFAT)相互作用促進(jìn)肥大[57,58]。例如，在非經(jīng)典Wnt/CaMKII信號(hào)途徑中，Dvl1激活CaMKII信號(hào)磷酸化HDAC4，HDAC4通過(guò)保守的氨基末端α-螺旋結(jié)構(gòu)域和HDAC5形成的復(fù)合物響應(yīng)CaMKII信號(hào)促進(jìn)HDAC5出核，激活MEF2轉(zhuǎn)錄因子的活性誘導(dǎo)心肌肥大[26]。而Dvl1引起的經(jīng)典Wnt信號(hào)傳導(dǎo)是通過(guò)形成β-catenin-TCF/ LEF復(fù)合物結(jié)合靶基因啟動(dòng)子，誘導(dǎo)Wnt信號(hào)的靶基因表達(dá)[59]，且非經(jīng)典Wnt/CaMKII信號(hào)與經(jīng)典Wnt信號(hào)傳導(dǎo)之間不相互影響。HDAC9敲除小鼠在出生8個(gè)月后出現(xiàn)心肌肥大現(xiàn)象，并且年幼的小鼠面對(duì)壓力更容易出現(xiàn)心肌肥大現(xiàn)象。鈣調(diào)神經(jīng)磷酸酶信號(hào)磷酸化HDAC9，激活的HDAC9出核減少與MEF2形成轉(zhuǎn)錄阻遏物，對(duì)病理性肥大信號(hào)做出反應(yīng)[34]。HDAC9的剪接變體MITR缺乏HDAC結(jié)構(gòu)域，但與全長(zhǎng)HDAC9蛋白一樣可與MEF2在細(xì)胞核內(nèi)相互作用形成轉(zhuǎn)錄阻遏物抑制MEF2的轉(zhuǎn)錄活性，調(diào)控心肌肥大[35]。

圖2 I類(lèi)HDACs調(diào)控心肌肥大的作用機(jī)制

圖3 II類(lèi)HDACs調(diào)控心肌肥大的作用機(jī)制

IIa類(lèi)HDACs家族也可以結(jié)合促肥大轉(zhuǎn)錄因子，通過(guò)調(diào)控促肥大轉(zhuǎn)錄因子的活性進(jìn)而抑制心肌細(xì)胞的肥大[60]。轉(zhuǎn)錄因子YY1可以抑制或激活多種基因的轉(zhuǎn)錄，其蛋白結(jié)構(gòu)與磷酸化的HDAC5結(jié)構(gòu)域結(jié)合。阻止HDAC5的核輸出將抑制YY1的活性，進(jìn)而下調(diào)肥大靶基因的表達(dá)，為抗病理性肥大提供保護(hù)機(jī)制[28]。IIa類(lèi)HDACs能與Myocardin相互作用形成轉(zhuǎn)錄復(fù)合物，通過(guò)抑制Myocardin-SRF轉(zhuǎn)錄復(fù)合物與靶基因啟動(dòng)子CArG元件的結(jié)合下調(diào)SRF轉(zhuǎn)錄因子促肌生成的活性，抑制SRF調(diào)控的肥大靶基因表達(dá)[61,62]。CaMKII信號(hào)磷酸化HDAC4，通過(guò)去乙?；饔媒档蚆EF2和SRF轉(zhuǎn)錄因子的活性下調(diào)肥大靶標(biāo)基因的表達(dá)[27]。

IIa類(lèi)HDACs還可以通過(guò)發(fā)揮“酶”的功能抑制心肌肥大[63]。磷酸化的HDAC2是促進(jìn)心肌肥大源動(dòng)力，而HDAC2磷酸化的過(guò)程也受到IIa類(lèi)HDACs乙?；挠绊?，涉及到由PCAF /HDAC5介導(dǎo)的乙?；腿ヒ阴；^(guò)程。HDAC5發(fā)揮去乙?；富钚匀ヒ阴；蚀笠蜃親DAC2，通過(guò)降低HDAC2乙酰化水平進(jìn)而下調(diào)HDAC2的磷酸化水平抑制心肌肥大表型[29]。在心肌細(xì)胞中，HDAC5的催化活性能抑制線粒體活性氧(reactive oxygen species, ROS)的產(chǎn)生，通過(guò)下調(diào)NRF2轉(zhuǎn)錄因子調(diào)控的抗氧化劑基因的表達(dá)來(lái)應(yīng)對(duì)外界強(qiáng)壓引發(fā)的生理性心肌肥大[30]。

神經(jīng)激素誘導(dǎo)心肌肥大關(guān)鍵機(jī)制就在IIa類(lèi)HDACs從細(xì)胞核移位導(dǎo)致MEF2C的去阻遏和促肥大基因的活化。內(nèi)皮素(endothelin, ET1)誘導(dǎo)的肥大機(jī)制一方面在于PKC/PKD的磷酸化HDAC5，通過(guò)誘導(dǎo)HDAC5出核降低對(duì)MEF2轉(zhuǎn)錄因子的阻遏促進(jìn)心肌肥大；另一方面在于降低腦利鈉肽、β-肌球蛋白重鏈、骨骼肌α-肌動(dòng)蛋白、心肌肌動(dòng)蛋等促肥大靶基因組蛋白H3去乙酰的表達(dá)水平[31]。ISO誘導(dǎo)的肥大機(jī)制一方面可以通過(guò)PKA信號(hào)和Gi-PI3K- Akt-CaMKII信號(hào)磷酸化IIa類(lèi)HDACs，通過(guò)誘導(dǎo)IIa類(lèi)HDAC出核激活MEF2信號(hào)下游肥大基因ANP和βMHC的表達(dá)[64,65]；另一方面通過(guò)β-腎上腺素信號(hào)介導(dǎo)氧化過(guò)程，通過(guò)增加細(xì)胞質(zhì)內(nèi)的ROS激活CaMKII磷酸化HDAC5，通過(guò)誘導(dǎo)HDAC5出核激活MEF2轉(zhuǎn)錄因子的活性，此過(guò)程獨(dú)立于PKD和PKA[32]。

IIb類(lèi)HDACs中，HDAC10尚無(wú)報(bào)導(dǎo)其與心肌肥大有關(guān)，但HDAC6已被發(fā)現(xiàn)參與調(diào)節(jié)心肌肥大。如前文所述，HDAC6可能參與醋酸去氧皮質(zhì)酮–鹽誘導(dǎo)的慢性高血壓大鼠的心肌肥大及纖維化[36]。盡管在注射Ang II后缺失HDAC6的小鼠與野生型小鼠一樣發(fā)生了心臟肥大和纖維化，但是前者的心臟功能維持長(zhǎng)達(dá)8周，而后者很快出現(xiàn)了收縮功能障礙。HDAC6的小分子抑制劑tubastatin A處理也呈現(xiàn)相似的表型。在TAC介導(dǎo)的壓力超負(fù)荷情況下，HDAC6缺失型小鼠還表現(xiàn)出改善的左心室功能。HDAC6抑制似乎部分通過(guò)增強(qiáng)肌原纖維協(xié)調(diào)收縮而維持收縮功能[37]。大鼠動(dòng)物實(shí)驗(yàn)的結(jié)果顯示，口服丁酸鈉可顯著減輕Ang II誘導(dǎo)的大鼠心臟肥大反應(yīng)，是通過(guò)以HDAC5/HDAC6依賴性方式抑制COX2/PGE2途徑的激活實(shí)現(xiàn)的[33]。

4 III類(lèi)HDACs在心肌肥大中的作用

III類(lèi)HDACs是一類(lèi)依賴于NADH的去乙酰化酶類(lèi)家族，從細(xì)菌到人類(lèi)高度保守，調(diào)節(jié)人類(lèi)多種代謝、應(yīng)激以及與衰老相關(guān)的過(guò)程，如糖尿病和心血管疾病等。心肌特異性敲除的小鼠出現(xiàn)糖尿病性心肌病癥狀，包括心臟肥大和功能障礙等缺陷、胰島素抗性和葡萄糖代謝異常等[38]。SIRT6已被證明通過(guò)催化組蛋白去乙?；瘉?lái)調(diào)控心肌肥大。在TAC手術(shù)或ISO注射后,基因敲除小鼠發(fā)展成心肌肥大和心力衰竭，而心肌特異性過(guò)表達(dá)的轉(zhuǎn)基因小鼠不發(fā)生心肌肥大。SIRT6與c-Jun形成復(fù)合物而特異性募集到胰島素樣生長(zhǎng)因子(insulin-like growth factor, IGF)信號(hào)相關(guān)基因啟動(dòng)子上，通過(guò)促使啟動(dòng)子中H3K9而非H3K14的去乙?；?，直接抑制IGF信號(hào)相關(guān)關(guān)鍵基因如Igf1r、Igf2r、Igf2、Akt1和Akt3等的轉(zhuǎn)錄，進(jìn)而抑制IGF-Akt信號(hào)引起的心肌肥大和心力衰竭[49]。但是，目前的研究結(jié)果顯示Ⅲ類(lèi)HDACs調(diào)控心肌肥大的作用更多地通過(guò)調(diào)節(jié)非組蛋白的去乙?；瘜?shí)現(xiàn)。SIRT1對(duì)介導(dǎo)與PIP3結(jié)合的Akt和PDK1的pleckstrin同源域的賴氨酸殘基進(jìn)行去乙?；?，增強(qiáng)了Akt和PDK1與PIP3的結(jié)合并促進(jìn)了Akt的活化。這一翻譯后修飾對(duì)于Akt的致癌作用以及其在體育鍛煉和Ang II誘導(dǎo)的心肌肥大肥大中的作用都非常重要；敲除SIRT1基因?qū)?dòng)劑誘導(dǎo)的小鼠心肌肥大具有很強(qiáng)的保護(hù)作用[39]。還有有結(jié)果顯示，在腹主動(dòng)脈縮窄術(shù)或PE誘導(dǎo)的心肌肥大大鼠中，SIRT1可抑制PKC-ζ的乙?；?，阻止其與磷酸肌醇依賴性激酶1的結(jié)合，降低PKC-ζ磷酸化而下調(diào)NF-κB、ERK1/2和ERK5的活性來(lái)抑制心肌肥大[40]。FGF2既可以通過(guò)提高SIRT1的去乙?；富钚源龠M(jìn)SIRT1 對(duì)LKB1的去乙酰化，進(jìn)一步激活A(yù)MPK活性；也可通過(guò)提高SIRT1的去乙酰基酶活性改變FoxO1轉(zhuǎn)錄因子活性，上調(diào)過(guò)氧化氫酶、Sod2、Bim靶基因的表達(dá)，從而減少ROS積累和心肌細(xì)胞的凋亡，緩解Ang II引起的心肌肥大[41]。化療藥物阿霉素(Doxo)會(huì)導(dǎo)致ROS產(chǎn)生增多、線粒體片段化，誘發(fā)心臟線粒體損傷和細(xì)胞死亡而引發(fā)心肌肥大。SIRT3的激活可保護(hù)線粒體免受損傷，從而保護(hù)心臟免受Doxo誘導(dǎo)的心臟毒性的影響[43]?；蚯贸娃D(zhuǎn)基因的小鼠模型的研究結(jié)果顯示，SIRT3是通過(guò)抑制細(xì)胞內(nèi)ROS水平來(lái)保護(hù)心臟免于發(fā)生心臟肥大和間質(zhì)纖維化的。SIRT3和Foxo3a能夠在體內(nèi)相互結(jié)合，以NAD依賴的方式使Foxo3a去乙?；?，掩蓋Foxo3a的磷酸化依賴性核輸出，使其在核內(nèi)不動(dòng)，從而促進(jìn)依賴于Fox3a的錳超氧化物歧化酶(MnSOD)和過(guò)氧化氫酶(Cat)的編碼基因轉(zhuǎn)錄，降低細(xì)胞內(nèi)ROS的水平，再通過(guò)MAPK/ERK和PI3K/Akt途徑抑制了Ras激活和其下游信號(hào)傳導(dǎo)，導(dǎo)致參與心臟肥大發(fā)展的轉(zhuǎn)錄因子(特別是GATA4和NFAT)、翻譯因子(特別是elf4E)以及核糖體蛋白S6P的活性受到抑制，從而抑制心肌肥大[44]。在基因敲除和轉(zhuǎn)基因小鼠模型中，外源NAD的抗肥大作用是通過(guò)激活SIRT3而不是SIRT1來(lái)介導(dǎo)的。SIRT3使LKB1脫乙酰基并激活，從而增強(qiáng)LKB1-AMPK途徑的活性，阻止了mTOR介導(dǎo)的蛋白質(zhì)合成[45]。SIRT2通過(guò)使激酶LKB1的48賴氨酸脫乙?；瘡亩龠M(jìn)LKB1的磷酸化并隨后激活A(yù)MPK而導(dǎo)致LKB1-AMPK信號(hào)傳導(dǎo)，敲除則降低AMPK的激活，促進(jìn)衰老相關(guān)和Ang II引起的心臟肥大[42]。SIRT4表現(xiàn)為提高ROS水平促進(jìn)心肌肥大。在Ang II刺激誘導(dǎo)的轉(zhuǎn)基因肥大小鼠模型中，SIRT4抑制線粒體中MnSOD與SIRT3結(jié)合，通過(guò)增加MnSOD乙酰化水平降低其活性，導(dǎo)致ROS積累進(jìn)而促進(jìn)肥大[46]。SIRT5通過(guò)對(duì)蛋白的去琥珀?；饔谜{(diào)控代謝抑制心肌肥大。SIRT5可調(diào)控賴氨酸去琥珀酰化，在基因敲除小鼠心臟中SIRT5的缺失導(dǎo)致ECHA酶的賴氨酸琥珀?；档突钚裕霈F(xiàn)脂肪酸代謝缺陷和ATP含量降低現(xiàn)象，并產(chǎn)生肥厚型心肌病[47]。在TAC引起的心肌肥大的模型中，SIRT5參與細(xì)胞氧化代謝的蛋白質(zhì)底物(丙酮酸脫氫酶和脂肪酸氧化酶)的去琥珀?；绊懸种破咸烟茄趸?、TCA循環(huán)、脂肪酸氧化，通過(guò)調(diào)控線粒體能量來(lái)應(yīng)對(duì)心臟的應(yīng)激反應(yīng)[48]。在心肌細(xì)胞特異性敲除基因的小鼠模型中，小鼠心臟肥大、心臟的收縮功能明顯降低。SIRT7通過(guò)與GATA4直接相互作用并促進(jìn)其脫乙?；⒔档虶ATA4的轉(zhuǎn)錄活性而發(fā)揮抗肥大作用[50]。

多種miRNA靶向HDACs在心肌肥大中起重要的調(diào)控作用。miR-21-3p抑制心肌肥大的作用靶點(diǎn)是HDAC8，在TAC和Ang II引起的心肌肥大模型中，下調(diào)的HDAC8降低Akt和Gsk3β磷酸化抑制肥大[25]。miR-22是心肌肥大和心臟重塑的關(guān)鍵調(diào)節(jié)因子，在TAC誘導(dǎo)心肌肥大的小鼠中，敲除miR-22促進(jìn)靶基因SERCA2a等的表達(dá)，或通過(guò)促進(jìn)PURB抑制SRF轉(zhuǎn)錄因子的活性，進(jìn)而抑制心肌肥大和心力衰竭[66]。反之，過(guò)表達(dá)miR-22則誘導(dǎo)心肌肥大，其中和被鑒定為miR-22下游靶標(biāo)基因[67]。miR-1可能通過(guò)靶向HADC4在甲狀腺激素誘導(dǎo)的心肌肥大中起作用。在新生大鼠心肌細(xì)胞以及Wistar大鼠中，甲狀腺激素刺激誘導(dǎo)心肌肥大時(shí)，miR-1的下調(diào)，同時(shí)伴隨HDAC4 表達(dá)增高；過(guò)表達(dá)miR-1可阻止新生大鼠心肌細(xì)胞中T3誘導(dǎo)的心肌肥大和HADC4 mRNA水平的下降；另外HDACs抑制劑處理則能有效抑制心肌肥大[68]。在Ang II和TAC引起的心肌肥大的細(xì)胞模型和小鼠模型中，miR-497的表達(dá)明顯降低，螢光素酶報(bào)告基因檢測(cè)結(jié)果表明是miR-497的直接靶基因[69]。

5 HDACs抑制劑的抗心肌肥大作用

目前，針對(duì)HDACs家族為靶標(biāo)的HDACs抑制劑在心肌肥大的治療上獲得有效研究進(jìn)展。廣譜HDAC抑制劑TSA在Ang II或主動(dòng)脈束帶引起的心肌肥大小鼠/大鼠模型中, 可降低心臟中ANP、α-tubulin、β-MHC和間質(zhì)纖維化基因的表達(dá)，明顯減弱心肌肥大現(xiàn)象，提高鼠的存活率[70]。TSA也能減輕異丙腎上腺素[71]、苯腎上腺素[71,72]誘導(dǎo)的心肌細(xì)胞肥大反應(yīng)。在IL-18誘導(dǎo)的小鼠心肌肥大模型中，TSA通過(guò)促進(jìn)PTEN-PI3K-AKT和MAPK信號(hào)通路中激酶(TGFβ、TNF-α、IFNγ和IL-6)及轉(zhuǎn)錄因子(Myc、p53、NFkB和HNF4A)的乙?；瘉?lái)改善心肌肥大現(xiàn)象[73,74]。在Ang II誘導(dǎo)的心肌肥大小鼠/大鼠模型中，TSA可通過(guò)抑制HDAC6活性而減輕心肌肥大反應(yīng)[33,37]。在Hop轉(zhuǎn)基因小鼠心肌肥大模型中，TSA通過(guò)抑制依賴HDAC2的SRF活性減輕心肌肥大反應(yīng)[75]。廣譜HDAC抑制劑丁酸鈉能夠有效減少苯腎上腺素誘導(dǎo)誘導(dǎo)的心肌細(xì)胞的肥大反應(yīng)[72]以及Ang II誘導(dǎo)的小鼠/大鼠心肌肥大反應(yīng)[33,37]。scriptaid[76]、CBHA[73,74]也顯示具有TSA類(lèi)似的抗心肌肥大作用。HDACs抑制劑SAHA可以減輕醋酸去氧皮質(zhì)酮-鹽誘導(dǎo)高血壓大鼠模型中相關(guān)的心血管的重塑，并改善心臟和血管的心血管結(jié)構(gòu)和功能(包括心室肥大)[77]。一些選擇性HDAC抑制劑也有抑制心肌肥大的效應(yīng)。I類(lèi)HDAC抑制劑丙戊酸或SK-7041可減輕Ang II或主動(dòng)脈束帶引起的小鼠/大鼠心肌肥大[70]。還有研究顯示丙戊酸通過(guò)減少心臟中的ROS和ANG II1型受體的表達(dá)及對(duì)鹽皮質(zhì)激素受體MR乙?；饔脕?lái)減輕肥大反應(yīng)，減弱自發(fā)性高血壓大鼠心臟的肥大和纖維化反應(yīng)[78]。丙戊酸也能通過(guò)抑制Hop轉(zhuǎn)基因小鼠的心肌肥大反應(yīng)[75]。丙戊酸鈉能有效阻斷肺動(dòng)脈束帶或單芥子堿注射誘導(dǎo)的大鼠右心室肥大[79]，以及醋酸去氧皮質(zhì)酮–鹽誘導(dǎo)的慢性高血壓大鼠的心肌肥大及纖維化反應(yīng)[24,80]。另一種I類(lèi)HDAC抑制劑Apicidin可有效減輕主動(dòng)脈束誘導(dǎo)的小鼠左室肥大和心臟纖維化現(xiàn)象，改善心臟收縮功能[81]。在不同的心肌肥大動(dòng)物模型中施用HDACs抑制劑治療心肌肥大取得了良好的效果，特別是泛抑劑TSA已經(jīng)有了一些臨床應(yīng)用報(bào)告[76,82]。但是HDAC抑制劑在人類(lèi)心肌肥大治療中會(huì)伴隨出現(xiàn)白細(xì)胞減少、貧血、骨髓抑制等副作用，且臨床研究數(shù)據(jù)較少，所以距離HDAC抑制劑在治療人類(lèi)心肌肥大方面的應(yīng)用還需要更多的臨床應(yīng)用研究。

6 結(jié)語(yǔ)與展望

HDACs家族在心臟的發(fā)育和心肌肥大的過(guò)程中扮演著重要的角色。其中I類(lèi)HDACs和IIa類(lèi)HDACs、III類(lèi)HDACs在調(diào)控心肌肥大中發(fā)揮著不同的作用。I類(lèi)HDACs通過(guò)直接下調(diào)抗肥大調(diào)節(jié)因子而促進(jìn)心肌肥大，或通過(guò)調(diào)控轉(zhuǎn)錄因子和酶活性調(diào)控心肌肥大；IIa類(lèi)HDACs通過(guò)細(xì)胞核和細(xì)胞質(zhì)之間穿梭減弱對(duì)MEF2轉(zhuǎn)錄因子活性的抑制，或通過(guò)抑制促肥大轉(zhuǎn)錄因子活性，或發(fā)揮去乙?；缸饔靡种菩募〖?xì)胞的肥大；III類(lèi)HDACs則通過(guò)調(diào)控肥大信號(hào)途徑、氧化代謝途徑的酶和轉(zhuǎn)錄因子活性，或發(fā)揮去琥珀化酶功能等多種途徑調(diào)控心肌肥大。雖然I類(lèi)HDACs在心肌肥大過(guò)程中起著重要的作用，但I(xiàn)Ia類(lèi)HDACs以多形式發(fā)揮著抑制心肌肥大的作用, 而近幾年III類(lèi)HDACs則通過(guò)氧化代謝途徑作用調(diào)控心肌肥大也成為研究熱點(diǎn)。HDACs抑制劑除了在治療腫瘤等代謝性疾病方面具有潛在的應(yīng)用價(jià)值[83]，目前研究表明一些HDAC抑制劑尤其是一些廣譜HDAC抑制劑已經(jīng)在阻止心肌肥大、纖維化、局部心肌缺血顯示出明顯的效果。

綜上所述，大量的研究證明HDACs在心肌肥大病理過(guò)程中發(fā)揮了重要的調(diào)節(jié)作用。雖然HDACs在體內(nèi)的作用靶點(diǎn)、參與不同肥大刺激因子誘導(dǎo)心肌肥大過(guò)程中的具體HDACs的作用和相互關(guān)系等問(wèn)題還有待進(jìn)一步解析，調(diào)控通路尚未完全闡明，與HDACs直接相互作用的其他心肌肥大調(diào)控因子還需要繼續(xù)鑒定，各種HDAC抑制劑的作用靶標(biāo)和精確效應(yīng)有待精細(xì)化研究，HDAC抑制劑的抑制效應(yīng)與靶HDAC的基因敲除表型之間的差異及其原因等重要問(wèn)題急待更深入的研究解決，但HDACs極有可能成為對(duì)心肌肥大和心臟重塑進(jìn)行有效臨床干預(yù)的新治療策略。

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The mechanism underlying histone deacetylases regulating cardiac hypertrophy

Lian Ren, Xiushan Wu, Yongqing Li

Cardiac hypertrophy is a compensatory response that occurs as a result of increased hemodynamic requirement in peripheral tissues. In the process of cardiac hypertrophy, the expression of different types of genes in different stages is transcriptionally regulated by multiple-level physiological and pathological signals. Histone acetylation, as the most extensive post-translational modification, is closely controlled by the antagonistic histone acetyltransferases (HAT) and histone deacetylases (HDACs). Recent studies have shown that HDACs, as a family of enzymes that inhibit transcription and contain highly conserved deacetylase domains, regulate gene expression during cardiac hypertrophy through a variety of pathways. In this review, we mainly summarize the research progress on histone deacetylase in cardiac hypertrophy. By elucidating the role and molecular mechanism of different HDACs in cardiac hypertrophy, it provides new ideas for the treatment of different types of cardiac hypertrophy and heart failure, and molecular targets for new drug design.

myocardial hypertrophy; post-translational modification; transcription process; histone deacetylases; molecular mechanism

2020-01-18;

2020-04-13

國(guó)家自然科學(xué)基金項(xiàng)目(編號(hào)：81470377)和湖南省生物發(fā)育工程及新產(chǎn)品研發(fā)協(xié)同創(chuàng)新中心項(xiàng)目(編號(hào)：2013-448-6)資助[Supported by the National Natural Science Foundation of China (No. 81470377), and Hunan Province Biological Development Engineering and New Product R & D Collaborative Innovation Center (No. 2013-448-6)]

任戀，在讀博士研究生，專(zhuān)業(yè)方向：分子遺傳。E-mail: 82287168@qq.com

李永青，博士，教授，研究方向：心臟發(fā)育與疾病的分子機(jī)制。E-mail: liyongqing2002cn@aliyun.com

10.16288/j.yczz.19-346

2020/4/28 8:44:03

URI: http://kns.cnki.net/kcms/detail/11.1913.R.20200427.1716.003.html

(責(zé)任編委: 楊中州)