方瀚黃石安
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芳香烴受體對(duì)心臟結(jié)構(gòu)與功能的影響
方瀚①黃石安②
【摘要】芳香經(jīng)受體(aryl hydrocarbon receptor,AhR)是存在于細(xì)胞胞質(zhì)內(nèi)的一種配體激活型轉(zhuǎn)錄因子,屬于堿性螺旋-環(huán)-螺旋(basic helix-loop-helix,bHLH)超家族中Per-Arnt-Sim同源域(Per-Arnt-Sim homology domain,PAS)蛋白亞型。芳香烴受體與相應(yīng)配體結(jié)合并被激活,并移位到細(xì)胞核內(nèi),與芳香烴受體核轉(zhuǎn)運(yùn)蛋白形成異二聚體復(fù)合物,此異二聚體可結(jié)合于相應(yīng)的DNA序列,引發(fā)下游目的基因的轉(zhuǎn)錄及表達(dá),產(chǎn)生一系列生物學(xué)效應(yīng)。本文將對(duì)芳香烴受體對(duì)心臟結(jié)構(gòu)與功能的影響作一綜述。
【關(guān)鍵詞】芳香經(jīng)受體; 心血管系統(tǒng); 多環(huán)芳烴
①廣東醫(yī)學(xué)院 廣東 湛江 524000
②廣東醫(yī)學(xué)院附屬醫(yī)院
First-author’s address:Guangdong Medical College,Zhanjiang 524000,China
心血管疾病不僅發(fā)病率高而且致死率高,嚴(yán)重威脅人類健康及生活水平。在中國,隨著人口老齡化加重,老年人的數(shù)量逐年增加,患有心血管疾病的患者也逐年增多,心血管疾病已經(jīng)逐步成為我國城鄉(xiāng)人群首位的死亡原因。無論是先天性心臟病等先天性疾病,亦或是心肌梗死、心肌炎等各種因素誘發(fā)的疾病,心肌細(xì)胞肥大、間質(zhì)細(xì)胞增殖、膠原組織增生等病理結(jié)構(gòu)的改變?cè)诩膊〉陌l(fā)生發(fā)展過程中起著關(guān)鍵性的作用,其最終都將影響心功能導(dǎo)致心功能不全。在心臟疾病的進(jìn)展過程中,有很多分子及信號(hào)通路參與其中,現(xiàn)已經(jīng)有大量研究報(bào)道芳香烴受體作為介導(dǎo)分子參與了其中的改變。芳香烴受體(aryl hydrocarbon receptor,AhR)是一種配體激活的轉(zhuǎn)錄因子,目前對(duì)于其的研究主要集中在腫瘤及免疫領(lǐng)域,但是隨著對(duì)AhR研究的深入,科學(xué)家們發(fā)現(xiàn)其與心血管疾病的發(fā)生和發(fā)展也有著很密切聯(lián)系,現(xiàn)本文就芳香烴受體對(duì)心臟結(jié)構(gòu)與功能的影響作一綜述。
AhR是一種基本的螺旋-環(huán)-螺旋結(jié)構(gòu)的轉(zhuǎn)錄因子,其作為關(guān)鍵的調(diào)節(jié)因子介導(dǎo)著多種分子信號(hào)通路的過程。例如胚胎發(fā)育、異生物質(zhì)代謝、免疫反應(yīng)和炎癥反應(yīng),以及腫瘤的發(fā)生[1]。AhR是一種泛素連接酶復(fù)合物的組成部分,可以調(diào)節(jié)選擇性靶蛋白的降解[2],其有幾個(gè)功能域,bHLH在NH2斷區(qū)域與DNA結(jié)合,PAS區(qū)域在bHLH的COOH-端附近,同時(shí),PAS由PAS-A和PAS-B組成。有研究表明,HSP90綁定在PAS-B上,結(jié)合AhR的配體蛋白極有可能是改變了HSP90/AhR復(fù)合物的結(jié)構(gòu),暴露出AhR的核定位信號(hào),從而使復(fù)合物進(jìn)行核轉(zhuǎn)移[3]。
芳香烴受體在沒有配體的時(shí)候作為細(xì)胞質(zhì)的復(fù)合蛋白存在,其復(fù)合物包括兩種分子伴侶:HSP90相互作用蛋白p23和抑免蛋白樣蛋白質(zhì)XAP2[4]。HSP90可能控制著AhR的激活[5],有研究報(bào)道,當(dāng)培養(yǎng)細(xì)胞時(shí)加入細(xì)胞抽提出的ARNT共培養(yǎng)時(shí),HSP90可以在AhR中釋放出來,而ARNT敲除的小鼠肝癌細(xì)胞就沒有這一現(xiàn)象[6]。亦有研究發(fā)現(xiàn)ARNT缺失小鼠由于其血管生成、對(duì)缺糖損傷的修復(fù)功能缺陷以及低氧導(dǎo)致其胚胎死亡[7]。當(dāng)在非激活形式的時(shí)候,AhR和各種各樣的伴侶蛋白在一起存在于細(xì)胞質(zhì)中。當(dāng)AhR被激活,很多解毒作用的基因被轉(zhuǎn)錄,包括編碼階段Ⅰ異型生物質(zhì)代謝細(xì)胞色素P450酶CYP1A1、 CYP1A2、CYP1B1、CYP2S1,階段Ⅱ酶尿苷二磷酸葡萄糖醛酸轉(zhuǎn)移酶UGT1A6,NAD(P)H依賴醌氧化還原酶1(NQO1),醛脫氫酶ALDH3A1和一些谷胱甘肽-S-轉(zhuǎn)移酶[8]。AhR包含的核定位信號(hào)和核輸出信號(hào)對(duì)于AhR在細(xì)胞核-細(xì)胞質(zhì)之間的穿梭是非常必要的,細(xì)胞核質(zhì)間的穿梭需要CYP1A1的誘導(dǎo)表達(dá),AhR的應(yīng)答基因CYP1A1在缺乏外源性配體的情況下,在非小細(xì)胞肺癌和前列腺癌中表達(dá)。無論在何種情況下,CYP1B1的表達(dá)都會(huì)伴隨著AhR表達(dá)和受體固有活性的增加[9]。CYP1B1而不是CYP1A1的水平與AhR過表達(dá)和持續(xù)的活性關(guān)系更加密切,在缺乏外源性配體的情況下,AhR的過表達(dá)在肺腺癌早期可以上調(diào)CYP1B1[10]。但是,懸浮的野生型Hepa-1細(xì)胞導(dǎo)致的核定位和AhR 的激活增加了CYP1A1的表達(dá)[11]。此外,細(xì)胞濃度低造成的細(xì)胞接觸的減少會(huì)增加AhR的轉(zhuǎn)錄活性。AhR轉(zhuǎn)錄活性的調(diào)節(jié)需要配體激活導(dǎo)致的鈣離子的改變,有研究表明,AhR的核聚集依賴于鈣蛋白酶的活性,用特異性抑制劑抑制鈣蛋白酶活性會(huì)阻礙AhR的轉(zhuǎn)錄活性[12]。此外,可以增加細(xì)胞內(nèi)鈣離子的奧體普拉會(huì)導(dǎo)致AhR應(yīng)答基因CYP1A1表達(dá)的升高。數(shù)據(jù)證明奧體普拉通過激活鈣離子引起了AhR核轉(zhuǎn)位。提高細(xì)胞內(nèi)鈣離子水平導(dǎo)致的AhR的活性 與增加Ca2+/鈣調(diào)蛋白(CAM)-依賴蛋白酶(CaMK)途徑的活性有關(guān),CaMK1α的抑制劑或者敲除TCDD的抑制會(huì)引起AhR的核轉(zhuǎn)位。
AhR的激動(dòng)劑有很多,最具有代表性的是色氨酸代謝產(chǎn)物以及2,3,7,8-四氯二苯并二惡英[13]。如色氨酸的降解產(chǎn)物L(fēng)-犬尿氨酸被干擾素-γ誘導(dǎo)酶吲哚胺-2.3-加雙氧酶催化后,作為一種AhR的激動(dòng)劑存在于弓形蟲患者體內(nèi)的很多組織[14]。隨著對(duì)AhR研究的深入,大量的AhR配體已經(jīng)逐步被發(fā)現(xiàn),其中包括合成物和環(huán)境中化學(xué)物質(zhì),飲食中存在的和內(nèi)源性復(fù)合物[15]。環(huán)境中的污染物包括平面鹵代芳香烴,合成多環(huán)芳香烴和二惡英類復(fù)合物,TCDD 是環(huán)境中大量存在的許多氯化芳香復(fù)合物的樣品。給嚙齒類動(dòng)物小劑量注射TCDD,會(huì)起到致癌物質(zhì)的作用,在很多地方引起腫瘤,例如肝臟、肺、硬腭、甲狀腺、舌頭、皮膚,但是不會(huì)引起腸的腫瘤[16]。內(nèi)源性配體包括靛藍(lán)類染料、花生四烯酸的代謝物、亞鐵血紅素和色氨酸。此外,AhR主要的拮抗劑包括CH223191,GNF351和31-41-二甲氧基-萘黃酮[17]。
關(guān)于芳香烴受體在腫瘤領(lǐng)域的研究認(rèn)為AhR有抗腫瘤的作用,并且可以在體內(nèi)以拮抗劑或興奮劑與配體結(jié)合的方式行自我調(diào)節(jié)[18]。而AhR在生長發(fā)育過程中的作用已經(jīng)在某些水平上得到了證實(shí),大部分的研究都是通過敲除AhR或部分削減AhR活性的轉(zhuǎn)基因小鼠來進(jìn)行的。AhR-/-小鼠展示出一系列在行為學(xué)、形態(tài)學(xué)和功能上的畸形,包括動(dòng)眼神經(jīng)的破壞,心肌病,血管肥大,胃增生,免疫缺失和繁殖困難[19-20]。不僅如此,最近的研究表明,AhR在很多生物學(xué)過程中起到了很重要的功能作用,例如調(diào)節(jié)T細(xì)胞的分化、細(xì)胞周期的調(diào)節(jié)應(yīng)激反應(yīng)的調(diào)節(jié)、炎癥反應(yīng)和分子的交互溝通[21-23]。更有研究表明,AhR還和高血壓、2型糖尿病和腫瘤有關(guān)[24-26]。
近幾年的研究表明AhR的表達(dá)對(duì)于心血管系統(tǒng)、消化系統(tǒng)、免疫系統(tǒng)的系統(tǒng)內(nèi)環(huán)境的平衡都是必需的[27]。AhR的功能不僅體現(xiàn)在其對(duì)異型生物質(zhì)中毒的反應(yīng),而且在生長發(fā)育和細(xì)胞增殖過程中也起到不可替代的作用。除了對(duì)異型生物質(zhì)毒性調(diào)節(jié)功能,AhR在一系列生物進(jìn)程中的功能也開始逐漸被認(rèn)識(shí),這與其靶基因在信號(hào)通路中對(duì)細(xì)胞周期和生長發(fā)育過程中的調(diào)節(jié)有關(guān)。AhR非必要但又十分重要的功能是其在控制與細(xì)胞增殖、死亡和分化過程中的控制平衡作用,如果失去其功能,將會(huì)導(dǎo)致疾病發(fā)生和發(fā)展,最終導(dǎo)致許多生物過程中的基因表達(dá)發(fā)生調(diào)節(jié)改變[28]。
多環(huán)芳烴(PAHs)是環(huán)境中普遍存在的污染物,具有一系列的毒性效應(yīng),包括致癌作用、誘導(dǎo)變異發(fā)生、對(duì)免疫和內(nèi)分泌功能的破壞以及致發(fā)育缺陷。在硬骨魚類中,心臟是PAH-毒性的目的靶器官之一,例如將胚胎暴露于含有PAHs的風(fēng)化原油中將會(huì)破壞心臟循環(huán)、出現(xiàn)房室傳導(dǎo)阻滯、心律失常等;苯丙[k]-熒蒽(BkF)和β-萘黃酮(BNF)會(huì)導(dǎo)致心包水腫[29]。AhR在對(duì)PAHs的心臟毒性調(diào)節(jié)中起到了一定的作用,但是也有研究表明在AhR-非依賴的機(jī)制中PAHs也可導(dǎo)致心臟毒性[30-31]?;谝陨涎芯炕A(chǔ),最新研究表明,AhR2-依賴的丙烯酸丁酯的毒性在部分上是通過打亂Ca2+的穩(wěn)定性調(diào)節(jié)的。維持足夠的Ca2+調(diào)節(jié)蛋白的濃度、細(xì)胞的Ca2+水平和精確的肌節(jié)功能對(duì)正常的心臟發(fā)育和生長起到了支持作用,因此,丙烯酸丁酯在Ca2+信號(hào)通路和收縮基因中的變化與發(fā)育的心臟畸形有直接的關(guān)系[32]。有研究表明,在小鼠飼養(yǎng)過程中一次性給于高劑量TCDD會(huì)導(dǎo)致小鼠的血壓緩慢上升[33],而另外有研究報(bào)道慢性暴露在TCDD中的小鼠將會(huì)出現(xiàn)心肌病和慢性動(dòng)脈炎發(fā)病率的增加及其發(fā)病率與的劑量的增長而增加[34]。最新的研究證實(shí),亞慢性TCDD暴露會(huì)增加全身動(dòng)脈血壓、左心室重量和壁的厚度、心血管超氧化物,增加以NO-依賴的血管舒張的減少為特征的內(nèi)皮功能紊亂,總之TCDD使得AhR持續(xù)激活會(huì)導(dǎo)致高血壓、心肌肥厚[35]。最近研究發(fā)現(xiàn),用TCDD處理正在分化的小鼠胚胎干細(xì)胞會(huì)激活A(yù)hR,抑制NKX2.5基因和其他心臟標(biāo)記物的表達(dá)。接著追蹤小鼠胚胎干細(xì)胞分化過程中加入TCDD后對(duì)心肌細(xì)胞標(biāo)記物表達(dá)的影響發(fā)現(xiàn),TCDD沉默了NKX2.5和其他心肌特異性基因的表達(dá)包括心肌肌鈣蛋白-T、α-和β-肌球蛋白重鏈,抑制跳動(dòng)心肌細(xì)胞的形成。根據(jù)染色質(zhì)免疫沉淀結(jié)果發(fā)現(xiàn),AhR是TCDD產(chǎn)生這些作用的關(guān)鍵調(diào)節(jié)器[36]。找到可能的基因-X-環(huán)境途徑中有機(jī)氯農(nóng)藥復(fù)合物導(dǎo)致先天心血管畸形中AhR起的重要作用,充分了解這些通路后將會(huì)為相關(guān)研究提供分子靶點(diǎn),以更好地理解AhR-調(diào)節(jié)的心臟毒性。除了NKX2.5外,還有更多基因在心臟發(fā)育中起到了更重要的作用,這些基因調(diào)節(jié)胎兒和出生后心臟的內(nèi)皮、平滑肌、心肌和間充質(zhì)細(xì)胞的增殖分化。這些基因大部分是信號(hào)通路中的一員,例如VEGF、NFATc1、BMP10、Notch、WNT/b-catenin、TGF-β和其他與AhR信號(hào)通路有關(guān)的基因[37]。TCDD可以導(dǎo)致斑馬魚的幼體心臟畸形、心衰、心包水腫、卵黃囊水腫、腦膜水腫、出血、顱面畸形、生長停滯和死亡[38]。
不僅環(huán)境中的污染物可以導(dǎo)致心臟結(jié)構(gòu)和功能的改變,在臨床上使用的藥物會(huì)有相似的副作用。有研究表明,一種臨床上使用的酪氨酸酶抑制劑吉非替尼,其主要可以誘導(dǎo)非小細(xì)胞肺癌中CYP1A1的mRNA,同時(shí)激活表皮生長因子受體(EGFR)[39]。此外,舒尼替尼通過非依賴配體的AhR的激活誘導(dǎo)人類乳腺癌MCF7細(xì)胞中CYP1A1基因的表達(dá)[40]。阿霉素(DOX)激活A(yù)hR使得AhR核轉(zhuǎn)移,與ARNT1形成二聚體,AhR-調(diào)節(jié)的基因表達(dá)升高,同時(shí),AhR活性的降低會(huì)增加DOX引起的心臟毒性,毒性與DOX代謝生成的氧自由基有關(guān)。DOX由線粒體呼吸鏈酶復(fù)合體Ⅰ的NADH脫氫酶導(dǎo)致的DOX的減少,會(huì)形成半醌自由基與分子氧作用形成超氧化物自由基。接著,氧化還原反應(yīng)會(huì)產(chǎn)生過氧化氫和羥基自由基。另外,DOX-鐵復(fù)合物的形成催化芬頓反應(yīng)導(dǎo)致ROS的產(chǎn)生。已經(jīng)有研究表明,ROS產(chǎn)生的減少可以減弱心臟中DOX的損害[41]。Volkova等[42]的研究發(fā)現(xiàn),AhR-/-心臟在用DOX處理后ROS的產(chǎn)生會(huì)增加。AhR的激活會(huì)導(dǎo)致階段Ⅰ (例如CYP1A1,CYP1A2,CYP1B1)和階段Ⅱ(例如GSTA1,NQO1)藥物代謝基因的上調(diào)表達(dá)。前者的基因產(chǎn)物與底物氧化和ROS的產(chǎn)生有關(guān),而后者參與了代謝物結(jié)合并具有抗氧化特性。在不同的組織中AhR-調(diào)節(jié)的階段Ⅰ和階段Ⅱ藥物代謝基因也不同。盡管AhR激活的基本作用是增加與異生物質(zhì)代謝有關(guān)的基因的表達(dá),但是對(duì)于AhR在心臟中的作用還不是非常明確,急性或者慢性攝入TCDD會(huì)導(dǎo)致收縮力損傷和心肌病。有些研究表明內(nèi)皮的AhR被激活是由于高糖血癥和剪切力的改變,AhR的缺失會(huì)降低血管內(nèi)皮生長因子的表達(dá),損傷血管的生成。AhR與DOX產(chǎn)生的心臟毒性有直接關(guān)系,AhR對(duì)DOX引起的傷害起到了心臟保護(hù)的作用。AhR的缺失與DOX引起的ROS產(chǎn)生的增加、p53的激活、心肌細(xì)胞的凋亡有關(guān)。
動(dòng)物生理和行為的生物周期節(jié)律在24 h循環(huán)的過程中是不斷變化的,在生理行為之下的是分子鐘。分子鐘在每個(gè)哺乳動(dòng)物細(xì)胞中都是固有的,并且形成了細(xì)胞自主節(jié)律,可以使細(xì)胞在周圍環(huán)境變化或應(yīng)急下得以應(yīng)對(duì)[43]。分子鐘是由一系列相互聯(lián)系的轉(zhuǎn)錄-翻譯正負(fù)反饋環(huán)組成的,可以使基因的表達(dá)、蛋白質(zhì)豐度、生理學(xué)過程和動(dòng)物行為產(chǎn)生節(jié)律性。腦和肌肉中的芳香烴受體核轉(zhuǎn)錄因子樣蛋白(Bmal1)是核心分子鐘轉(zhuǎn)錄因子之一[44]。在心血管系統(tǒng)中,Bmal1-/-小鼠在心率和血壓上缺少晝夜變化,導(dǎo)致其整個(gè)生理循環(huán)中始終保持低血壓[45]。有研究表明[46],Bmal1-/-小鼠的心肌細(xì)胞將出現(xiàn)心肌質(zhì)量短暫的上升,心肌的擴(kuò)大,最后心衰,并在36周齡左右時(shí)導(dǎo)致死亡。心肌收縮功能障礙出現(xiàn)伴隨著兩種MHC的轉(zhuǎn)錄的下調(diào),表明肌球蛋白基因的表達(dá)在轉(zhuǎn)錄和后轉(zhuǎn)錄都發(fā)生了變化。Bmal1-/-小鼠的心臟正常肌小節(jié)的缺失,并變?yōu)榧÷?lián)蛋白的成分,同時(shí)顯得更為堅(jiān)硬。由此證實(shí),Bmal1通過調(diào)節(jié)肌聯(lián)蛋白和MHC在分子生物鐘中保持心肌結(jié)構(gòu)和功能的完整性起到了重要的作用。
隨著研究的不斷深入進(jìn)行,可以發(fā)現(xiàn)對(duì)于AhR的了解也更加深入。AhR不僅在免疫系統(tǒng)、腫瘤的發(fā)生發(fā)展中扮演著重要角色,其在心血管系統(tǒng)中的作用也不容小覷?,F(xiàn)有的文獻(xiàn)中,對(duì)于AhR與心臟結(jié)構(gòu)和功能的研究大多集中于其配體以及CYP1A1的基因研究,其具體作用機(jī)制還未知。AhR對(duì)心臟結(jié)構(gòu)和功能的影響方面還需要進(jìn)一步探討研究,找尋兩者之間的關(guān)系,為治療心臟疾病提供更多理論基礎(chǔ)和臨床思路。
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The Influence of Aryl Hydrocarbon Receptor on Cardiac Structure and Function
FANG Han,HUANG Shi-an.//Medical Innovation of China,2016,13(11):140-144
【Abstract】The aryl hydrocarbon receptor (AhR) is an evolutionarily old transcription factor belonging to the Per-ARNT-Sim-basic helix-loop-helix protein family.Ligand binding causes AHR to translocate to the nucleus,shed the chaperone proteins,and bind with aryl hydrocarbon receptor nuclear translocator (ARNT).The AHR-ARNT heterodimer binds to dioxin response elements in the promoter region of downstream target genes and directly upregulates their expression.This article will define the mechanisms of AhR responsible for the lifelong cardiovascular malformations.
【Key words】Aryl hydrocarbon receptor; Cardiovascular system; Polycyclic aromatic hydrocarbons
通信作者:黃石安
doi:10.3969/j.issn.1674-4985.2016.11.040
收稿日期:(2015-11-16) (本文編輯:蔡元元)