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芳香烴受體在心房顫動(dòng)患者心房組織中的表達(dá)及意義*

2017-05-19 01:05雷建明郭靜文肖銘漢
中國(guó)病理生理雜志 2017年5期
關(guān)鍵詞:心耳先心病膠原

雷建明, 肖 驊, 李 強(qiáng), 魏 瀟, 郭靜文, 肖銘漢

(重慶醫(yī)科大學(xué)附屬第一醫(yī)院心血管內(nèi)科, 重慶 400016)

芳香烴受體在心房顫動(dòng)患者心房組織中的表達(dá)及意義*

雷建明, 肖 驊△, 李 強(qiáng), 魏 瀟, 郭靜文, 肖銘漢

(重慶醫(yī)科大學(xué)附屬第一醫(yī)院心血管內(nèi)科, 重慶 400016)

目的: 檢測(cè)芳香烴受體(AhR)在風(fēng)濕性心臟病(風(fēng)心病)心房顫動(dòng)患者右心耳組織中的表達(dá),探討其在心房纖維化中的作用及意義。方法: 取風(fēng)心病換瓣手術(shù)患者的右心耳組織為實(shí)驗(yàn)組,其中風(fēng)心病竇性心律組25例和風(fēng)心病慢性房顫組11例;取先天性心臟病(先心病)心臟手術(shù)患者的右心耳組織12例作為對(duì)照組。采用Masson染色法檢測(cè)右心耳組織膠原含量,采用免疫組化技術(shù)檢測(cè)AhR、AhR核轉(zhuǎn)位蛋白(ARNT)和CYP1A1蛋白的表達(dá)和分布,采用實(shí)時(shí)熒光定量PCR檢測(cè)AhR、ARNT和CYP1A1的mRNA表達(dá),采用Western blot檢測(cè)AhR、ARNT和CYP1A1的蛋白表達(dá)。 結(jié)果: 與先心病組相比, 風(fēng)心病竇律組和風(fēng)心病慢性房顫組膠原含量和AhR、ARNT、CYP1A1的表達(dá)明顯增高;與風(fēng)心病竇律組相比,風(fēng)心病慢性房顫組膠原含量和AhR、ARNT、CYP1A1的表達(dá)明顯增高(P<0.05)。結(jié)論: 風(fēng)心病患者心房組織中AhR 的表達(dá)與纖維化程度相關(guān); AhR/ARNT/CYP1A1在風(fēng)心病患者中表達(dá)增加,可能參與風(fēng)心病心房纖維化的發(fā)生發(fā)展。

芳香烴受體; 心房顫動(dòng); 纖維化

心房顫動(dòng)(atrial fibrillation,AF)簡(jiǎn)稱房顫,是臨床上最常見(jiàn)的心率失常之一,發(fā)病率和死亡率隨年齡逐漸增加,尤其合并卒中和心衰等并發(fā)癥時(shí)更高[1]。引起房顫最常見(jiàn)的原因是風(fēng)濕性心臟病(rheumatic heart disease, RHD),該病極易引起瓣膜病變,進(jìn)而引發(fā)房顫[2]。房顫的發(fā)生過(guò)程中存在結(jié)構(gòu)重構(gòu),心房纖維化是結(jié)構(gòu)重構(gòu)最突出的特征,然而心房纖維化的具體機(jī)制還不明確[3]。

芳香烴受體(aryl hydrocarbon receptor,AhR)是一種配體激活性轉(zhuǎn)錄蛋白,激活后與AhR核轉(zhuǎn)位蛋白(AhR nuclear translocator,ARNT)結(jié)合,可調(diào)節(jié)細(xì)胞色素酶P450家族成員之一CYP1A1的表達(dá)[4-5]。有研究表明激活A(yù)hR可誘導(dǎo)小鼠肝纖維化[6]。AhR在人體直腸等部位有表達(dá)且發(fā)揮作用[7],但在心房中是否表達(dá)發(fā)揮作用卻未見(jiàn)報(bào)道。為此,我們收集先心病與風(fēng)心病患者在體外循環(huán)手術(shù)中收集右心耳標(biāo)本,檢測(cè)組織膠原含量與AhR的表達(dá),探討AhR在心房纖維化中作用,為房顫的相關(guān)防治提供新的方向。

材 料 和 方 法

1 材料

1.1 研究對(duì)象 在這項(xiàng)研究中總共選入了48位患者,男17例,女31例,平均年齡為(42.77±14.24)歲。這些患者都是在2015.04~2016.03期間在重慶醫(yī)科大學(xué)附屬第一醫(yī)院進(jìn)行體外循環(huán)手術(shù),排除合并有冠心病、高血壓以及糖尿病的患者。將患者分成3組:先天性心臟病(congenital heart disease, CHD)竇性心律(CHD+sinus rhythm)組12例;RHD竇性心律(RHD+sinus rhythm)組25例;RHD持續(xù)性房顫(RHD+cAF)組11例。術(shù)前通過(guò)超聲心動(dòng)圖檢測(cè)左室前后徑、左室舒張末徑、右房橫徑和射血分?jǐn)?shù)。在進(jìn)行研究之前,均已通過(guò)患者或患者家屬簽字同意。所有知情同意書以及協(xié)議都通過(guò)了本院倫理委員會(huì)批準(zhǔn)。

1.2 右心耳組織取樣 在體外循環(huán)手術(shù)進(jìn)行時(shí),于手術(shù)室外即時(shí)接收體外循環(huán)手術(shù)中剪除的右心耳組織 約100 mg。將右心耳組織用冰盒運(yùn)送至實(shí)驗(yàn)室,以生理鹽水清洗,錫箔紙包裹,放入凍存管于-80 ℃保存。

1.3 主要試劑 抗 AhR和CYP1A1抗體(Abcam);抗ARNT抗體(CST);抗β-actin抗體(Proteintech);總RNA提取試劑盒、RNA逆轉(zhuǎn)錄試劑盒、實(shí)時(shí)熒光定量PCR試劑盒以及AhR、ARNT、CYP1A1和β-actin的引物(TaKaRa);Masson染色試劑盒(南京建成科技有限公司);免疫組化試劑盒(北京中杉金橋生物技術(shù)有限公司)。

2 主要方法

2.1 Masson染色 使用Masson染色試劑盒進(jìn)行Masson染色。石蠟切片脫蠟,入95%、70%、30%乙醇各2 min,蒸餾水2 min。40 ℃水中漂洗2次,各30 s。R1核染液染色60 s,沖洗液沖洗30 s。R2漿染液染色60 s,沖洗液沖洗30 s。R3黃色讓葉分色8 min,棄去分色液。R4藍(lán)色復(fù)染液染色5 min,無(wú)水乙醇沖洗干凈。中性樹脂封固,鏡下觀察拍照。每張切片在顯微鏡下隨機(jī)選取5個(gè)高倍視野(×200)。用Image-Pro Plus 6.0軟件,測(cè)定膠原容積分?jǐn)?shù)(collage volume fraction,CVF)=(膠原面積/所測(cè)視野面積),取平均值。

2.2 免疫組化 采用免疫組化方法檢測(cè)組織中蛋白表達(dá)情況。組織固定后,脫水切片,烘烤,泡缸,用SP9001處理進(jìn)行組化操作,孵 I 抗AhR(1∶100)、ARNT(1∶100)和CYP1A1(1∶50)。4 ℃過(guò)夜,孵 II 抗,DAB顯色,蘇木精染色,晾干,封片,顯微鏡下觀察拍照。每張切片在顯微鏡下隨機(jī)選取5個(gè)高倍視野(×400)。

2.3 Western blot 組織蛋白稱重記錄后放入勻漿管,在冰上剪碎組織。RIPA+PMSF(100∶1)裂解組織30 min,4 ℃離心5 min,收取上清液,BCA法測(cè)定樣品蛋白濃度。SDS-PAGE凝膠電泳分離、電轉(zhuǎn)至PVDF膜(Millipore),5%脫脂奶粉室溫封閉1 h,I 抗(AhR 1∶2 000,ARNT 1∶1 000,CYP1A1 1∶100,β-actin 1∶1 000)4 ℃孵育過(guò)夜,IgG II 抗(1∶7 500)室溫孵育1 h,ECL法顯色。以β-actin作為內(nèi)參照。電泳條帶灰度值使用實(shí)驗(yàn)室儀器自帶軟件Image Lab (Bio-Rad)進(jìn)行分析,以目的條帶灰度值與β-actin條帶灰度值之比表示目的蛋白的相對(duì)表達(dá)量。

2.4 實(shí)時(shí)熒光定量PCR 將右心房組織在冰上勻漿裂解,用總RNA提取試劑根據(jù)說(shuō)明書提取總RNA。用逆轉(zhuǎn)錄試劑盒將RNA逆轉(zhuǎn)錄。在實(shí)驗(yàn)室機(jī)器(Lab7500)上進(jìn)行10 μL體系擴(kuò)增。引物序列見(jiàn)表1。以β-actin為內(nèi)參照。反應(yīng)體系10 μL,PCR擴(kuò)增條件為:95 ℃ 30 s; 95 ℃ 5 s,60 ℃(AhR、ARNT和CYP1A1)/62 ℃(ANP)退火30 s,40個(gè)循環(huán); 65 ℃緩慢升高至95 ℃,每5 s增加0.5 ℃,分析熔解曲線。擴(kuò)增得到的Ct值使用2-ΔΔCt法計(jì)算目的mRNA的相對(duì)表達(dá)量。

3 統(tǒng)計(jì)學(xué)處理

使用SPSS 20.0統(tǒng)計(jì)軟件進(jìn)行數(shù)據(jù)分析。計(jì)量資料用均值±標(biāo)準(zhǔn)差(mean±SD)表示。多組間比較采用單因素方差分析(one-way ANOVA)法。以P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

表1 引物序列

結(jié) 果

1 患者分組及一般情況

與先心病竇律組相比,風(fēng)心病竇律及房顫組年齡、左房前后徑、左室舒張末徑明顯增加,右房橫徑明顯減??;與風(fēng)心病竇律組相比,風(fēng)心病持續(xù)性房顫組左房前后徑明顯增加,右房橫徑明顯增大(P<0.05)。射血分?jǐn)?shù)在3組間并無(wú)顯著差異,見(jiàn)表2。

表2 患者一般情況及超聲心動(dòng)圖結(jié)果

LAD: left atrial dimension; LVEDD: left ventricular end-diastolic dimension; RAD: right atrial dimension; LVEF: left ventricular ejection fraction.*P<0.05vsCHD+sinus rhythm;#P<0.05vsRHD+sinus rhythm.

2 組織膠原容積分?jǐn)?shù)

風(fēng)心病持續(xù)性房顫組心房組織CVF比風(fēng)心病竇律患者組及先心病竇律組明顯增高,風(fēng)心病竇律組CVF值比先心病竇律患者組明顯增高(P<0.05),見(jiàn)圖1。

3 AhR/ARNT/CYP1A1在組織中的分布

AhR/ARNT/CYP1A1蛋白在3組患者組織中均有表達(dá),3種蛋白主要分布于胞漿。與先心病竇律組相比,風(fēng)心病竇律組及持續(xù)性房顫組表達(dá)增加,其中持續(xù)性房顫組增加更為明顯,見(jiàn)圖2。

4 AhR/ARNT/CYP1A1的蛋白表達(dá)

與先心病竇性心律組相比,AhR、ARNT和CYP1A1表達(dá)水平在風(fēng)心病竇律組及風(fēng)心病持續(xù)性房顫組明顯升高;與風(fēng)心病竇律組相比,風(fēng)心病持續(xù)性房顫組明顯升高(P<0.05),見(jiàn)圖3。

5 AhR/ARNT/CYP1A1 的mRNA相對(duì)表達(dá)

AhR/ARNT/CYP1A1在風(fēng)心病房顫組與風(fēng)心病竇律組中的mRNA表達(dá)都顯著高于先心病竇律組,風(fēng)心病持續(xù)性房顫組AhR/ARNT/CYP1A1的mRNA表達(dá)水平都明顯高于風(fēng)心病竇律組(P<0.05),見(jiàn)圖4。

6 相關(guān)性分析

AhR在風(fēng)心病患者中的蛋白表達(dá)水平與CVF呈正相關(guān)(r=0.67,P<0.05);AhR蛋白表達(dá)與ARNT蛋白表達(dá)呈正相關(guān)(r=0.941,P<0.01);AhR與CYP1A1蛋白表達(dá)呈正相關(guān)(r=0.939,P<0.01)。

Figure 1.Determination of collagen volume fraction (CVF) in different groups by Masson’s trichrome staining (×200). Mean±SD.n=5.*P<0.05vsCHD+sinus rhythm;#P<0.05vsRHD+sinus rhythm.

圖1 膠原染色結(jié)果

Figure 2.Immunohistochemical analysis of AhR, ARNT and CYP1A1 in CHD+sinus rhythm group, RHD+sinus rhythm group and RHD+cAF group (×400). Brown or yellow stained proteins mainly distributed throughout the cytoplasm of myocardial cells, and their expression increased gradually.

圖2 免疫組化結(jié)果

Figure 3.Comparison of the relative protein expression of AhR, ARNT and CYP1A1 among groups. Mean±SD.n=3.*P<0.05vsCHD+sinus rhythm;#P<0.05vsRHD+sinus rhythm.

圖3 蛋白表達(dá)結(jié)果

討 論

近年來(lái),房顫的發(fā)病率和死亡率逐漸升高,造成了巨大的社會(huì)負(fù)擔(dān)[8]。繼發(fā)于風(fēng)濕性心臟病的房顫很常見(jiàn),它能夠損害心功能、增加體循環(huán)栓塞的風(fēng)險(xiǎn)[2]。在將來(lái)房顫會(huì)有更高的發(fā)病率[9]。

心房纖維化是房顫最顯著的結(jié)構(gòu)改變[3]。在本研究中心房組織纖維化程度在先心病竇律組、風(fēng)心病竇律組、房顫組逐漸升高,左房舒張末徑也相應(yīng)增大,同樣說(shuō)明心房纖維化與房顫相關(guān)。此發(fā)現(xiàn)與Zhang等[10]、Li等[11]的實(shí)驗(yàn)結(jié)果符合。何文聰?shù)萚12]在研究纖維化與縫隙連接重構(gòu)關(guān)系時(shí)也有類似發(fā)現(xiàn)。風(fēng)心病房顫組右房橫徑比風(fēng)心竇律組明顯增高,說(shuō)明房顫加深心房病變,而先心病組右房橫徑更高,原因可能是大部分入選先心病人為房間隔缺損,且年齡較大。這些病人,右房比風(fēng)心病組更大,心率卻是竇律,心房纖維化程度較低,這進(jìn)一步說(shuō)明房顫與纖維化密切相關(guān)。

Figure 4.Comparison of the relative mRNA expression of AhR, ARNT and CYP1A1 among groups. Mean±SD.n=5.*P<0.05vsCHD+sinus rhythm;#P<0.05vsRHD+sinus rhythm.

圖4 各組mRNA比值

近期研究發(fā)現(xiàn) AhR參與細(xì)胞分化、組織重構(gòu)、免疫調(diào)節(jié)等過(guò)程[13]。AhR/ARNT/CYP1A1是一經(jīng)典通路,參與纖維化等多種調(diào)節(jié)。Poormasjedi-Meibod等[14]研究表明在真皮成纖維細(xì)胞中AhR/ARNT/CYP1A1參與纖維化。Antos等[15]研究發(fā)現(xiàn)TCDD刺激AhR/ARNT/CYP1A1在卵巢中表達(dá)增加,發(fā)現(xiàn)了通過(guò)CYP1A1作為靶點(diǎn)解毒的可能性。涉及AhR的基礎(chǔ)研究大部分都是以動(dòng)物作為模型[16-17],本研究首次在人體心臟組織中發(fā)現(xiàn)AhR的表達(dá),且發(fā)現(xiàn)在風(fēng)心病患者中表達(dá)顯著高于先心病患者,提示AhR可能也是心臟疾病的一個(gè)重要因素。在本研究中AhR的表達(dá)在先心病竇律組、風(fēng)心病竇律組、風(fēng)心病慢性房顫組中逐漸升高,與心房纖維化程度一致。這也與Pierre等[6]在TCDD刺激小鼠肝臟細(xì)胞纖維化后,AhR蛋白及mRNA表達(dá)增加的結(jié)果相符。Xue等[17]也在研究中發(fā)現(xiàn)AhR參與調(diào)節(jié)小鼠胰腺纖維化。這些研究結(jié)果提示AhR可能參與心房纖維化的發(fā)生發(fā)展。ARNT是AhR核轉(zhuǎn)運(yùn)蛋白,是AhR相關(guān)信號(hào)通路的一個(gè)重要部分,許多基因調(diào)控都是通過(guò)AhR/ARNT介導(dǎo)的[18-20]。本研究中在3個(gè)組ARNT蛋白表達(dá)趨勢(shì)與AhR趨勢(shì)相同,呈正相關(guān)。提示AhR可能是通過(guò)介導(dǎo)ARNT參與心房纖維化。CYP1A1是細(xì)胞色素酶P450家族成員之一,在化學(xué)物質(zhì)代謝中起著重要作用,也是AhR/ARNT的一個(gè)下游調(diào)控基因[19]。Yaming等[21]研究發(fā)現(xiàn)CYP1A1基因在口腔黏膜下層纖維化中起重要作用,Ghosh等[22]也發(fā)現(xiàn)CYP1A1增加口腔黏膜下層纖維化的風(fēng)險(xiǎn)。本研究中,纖維化組織中CYP1A1蛋白表達(dá)趨勢(shì)與AhR/ARNT蛋白表達(dá)趨勢(shì)相一致,呈正相關(guān)。提示CYP1A1可能是AhR下游調(diào)控心房纖維化的關(guān)鍵環(huán)節(jié),可能成為治療風(fēng)心病房顫患者防治心房纖維化的重要靶點(diǎn)。

綜上所述,AhR/ARNT/CYP1A1信號(hào)通路可能參與了風(fēng)心病房顫患者心房纖維化的發(fā)生發(fā)展。本研究證實(shí)了AhR在人體心房組織中的表達(dá),并發(fā)現(xiàn)AhR的表達(dá)與組織纖維化程度相關(guān),擴(kuò)充了在人體心臟領(lǐng)域中對(duì)AhR的研究,豐富了心房纖維化的可能發(fā)生機(jī)制,也為房顫的藥物防治提供新的理論基礎(chǔ)。在后續(xù)的實(shí)驗(yàn)中,我們將進(jìn)行細(xì)胞水平實(shí)驗(yàn),并且繼續(xù)收集標(biāo)本,收取足夠的風(fēng)心病陣發(fā)性房顫病例作為風(fēng)心病陣發(fā)性房顫組。

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(責(zé)任編輯: 林白霜, 羅 森)

Expression and significance of aryl hydrocarbon receptor in atrial tissues of patients with atrial fibrillation

LEI Jian-ming, XIAO Hua, LI Qiang, WEI Xiao, GUO Jing-wen, XIAO Ming-han

(DepartmentofCardiology,TheFirstAffiliatedHospitalofChongqingMedicalUniversity,Chongqing400016,China.E-mail:xiaohua197408@163.com)

AIM: To investigate the expression of aryl hydrocarbon receptor (AhR) in atrial tissues of the patients with rheumatic heart disease (RHD), and the effects of AhR on rheumatic atrial fibrosis. METHODS: Right atrial specimens obtained from the patients with RHD requiring valve replacement surgery were divided into chronic atrial fibrillation (RHD+cAF,n=11) group and sinus rhythm (RHD+sinus rhythm,n=25) group. The patients with congenital heart disease (CHD) and sinus rhythm (CHD+sinus rhythm,n=12) who underwent heart surgery served as controls. The collagen volume fraction in the atrial specimens was examined by Masson’s trichrome staining. The protein expression and distribution of AhR, AhR nuclear translocator (ARNT) and CYP1A1 were detected by the methods of immunohistochemistry and Western blot. The mRNA expression of AhR, ARNT and CYP1A1 was detected by real-time fluorescence quantitative PCR. RESULTS: Compared with CHD+sinus rhythm group, the collagen content and the expression of AhR, ARNT and CYP1A1 were significantly increased in RHD+sinus rhythm group and RHD+cAF group. Compared with RHD+sinus rhythm group, the collagen content and the expression of AhR, ARNT and CYP1A1 were significantly increased in RHD+cAF group (P<0.05). CONCLUSION: The expression of AhR is correlated with the degree of fibrosis. The expression of AhR/ARNT/CYP1A1 is increased in atrial tissues of patients with RHD, suggesting that AhR/ARNT/CYP1A1 should be involved in atrial fibrosis of the patient with RHD.

Aryl hydrocarbon receptor; Atrial fibrillation; Fibrosis

1000- 4718(2017)05- 0826- 06

2016- 12- 19

2017- 03- 16

國(guó)家自然科學(xué)基金資助項(xiàng)目(No. 81300140)

R363

A

10.3969/j.issn.1000- 4718.2017.05.010

雜志網(wǎng)址: http://www.cjpp.net

△通訊作者 Tel: 023-89011565; E-mail: xiaohua197408@163.com

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