本文選題：心房顫動(dòng) + 心房纖維化　； 參考：《重慶醫(yī)科大學(xué)》2016年博士論文

【摘要】：背景:心房顫動(dòng)(Atrial fibrillation,AF,簡(jiǎn)稱(chēng)房顫),是臨床上最常見(jiàn)且難以治療、易復(fù)發(fā)的一種心律失常,已成為人類(lèi)心血管疾病中的一大流行病。多種疾病例如缺血性、瓣膜性、炎癥性和老年退化性心臟疾病、高血壓等均易引發(fā)房顫,然而目前房顫的治療效果尚不盡如人意。大量研究已證實(shí)腎素-血管緊張素系統(tǒng)(Renin angiotensin system,RAS)在房顫的發(fā)生與維持中被不同程度地激活。血管緊張素II(Angiotensin II,Ang II)是RAS最重要的效應(yīng)分子,具有收縮血管、促進(jìn)纖維化增生和心肌肥大等效應(yīng),它能被血管緊張素轉(zhuǎn)換酶2(Angiotensin converting enzyme 2,ACE2)轉(zhuǎn)化成為有保護(hù)性效應(yīng)的血管緊張素-(1-7)[Angiotensin-(1-7),Ang-(1-7)]。新近研究表明,過(guò)表達(dá)ACE2能拮抗Ang II介導(dǎo)的心房重構(gòu)效應(yīng)。心房重構(gòu)是房顫發(fā)生和維持的基本機(jī)制,改良心房基質(zhì)成為防治房顫的基礎(chǔ)環(huán)節(jié)。有研究表明,Rac1在心肌細(xì)胞中可能經(jīng)上調(diào)結(jié)締組織生長(zhǎng)因子(Connective Tissue Growth Factor,CTGF)、N-Cadherin及Cx43這一途徑促進(jìn)了心臟纖維化及心房重構(gòu);Rad(Ras Associated with Diabetes)GTPase在心臟中能抑制CTGF的轉(zhuǎn)錄,經(jīng)Rho/Rhokinase途徑調(diào)節(jié)細(xì)胞骨架的重塑。然而,在房顫中Rac1和Rad GTPase的動(dòng)態(tài)平衡的調(diào)節(jié)機(jī)制尚不明確,過(guò)表達(dá)ACE2改善心房纖維化的機(jī)制需進(jìn)一步探討。目的:本研究擬建立犬心房快速起搏模型,應(yīng)用心房外膜涂抹攜帶有ACE2基因的腺病毒的方法探討心房過(guò)表達(dá)ACE2對(duì)改善犬心房快速起搏所致的心房重構(gòu)的影響及其分子機(jī)制。方法:入選28只成年健康的雜種犬(22±2Kg,雌雄不拘),隨機(jī)分為4組,每組7只:Sham組(假手術(shù)組)、AF-Control組(心房快速起搏對(duì)照組)、AF-EGFP組(心房快速起搏+涂染Ad-EGFP腺病毒)及AF-ACE2組(心房快速起搏+涂染Ad-ACE2腺病毒)。其中AF-ACE2組與AF-EGFP組犬心房外膜分別涂染帶有ACE2和EGFP的腺病毒,Sham組與AF-Control組犬不涂染腺病毒。除Sham組外,AF-Control組、AF-EGFP組和AF-ACE2組均予以持續(xù)心房快速起搏(450次/min)。2周后,4組犬行第一次開(kāi)胸手術(shù)及心內(nèi)電生理檢查(Electrophysiological Study,EP),進(jìn)行基因涂染。轉(zhuǎn)染3周后行第二次開(kāi)胸手術(shù)及EP檢查,隨后處死,取心房組織標(biāo)本進(jìn)行一下研究:應(yīng)用蘇木精-伊紅(Hematoxylin-Eosin,HE)染色和天狼猩紅染色評(píng)價(jià)心房快速起搏所致的組織病理學(xué)改變;應(yīng)用免疫印跡技術(shù)評(píng)價(jià)RAS成員AT1R、AT2R、Apelin和Aplnr的表達(dá),以探討過(guò)表達(dá)ACE2對(duì)RAS系統(tǒng)的影響;應(yīng)用免疫組織化學(xué)方法和免疫印跡技術(shù)評(píng)價(jià)Rac1、Rad GTPase和Gem的表達(dá),應(yīng)用免疫印跡技術(shù)和免疫組織化學(xué)熒光方法評(píng)價(jià)CTGF、α-SMA和N-Cadherin的表達(dá),應(yīng)用實(shí)時(shí)熒光定量RT-PCR方法評(píng)價(jià)c-jun、c-myc和c-fos的基因表達(dá),以探討過(guò)表達(dá)ACE2對(duì)心房快速起搏所致的心房纖維化重構(gòu)的影響。結(jié)果:兩次開(kāi)胸手術(shù)中心內(nèi)電生理檢查結(jié)果相比,第二次手術(shù)中AF-Control組、AF-EGFP組及AF-ACE2組犬心房ERP均顯著降低,AERP頻率適應(yīng)性也顯著下降,而Sham組犬心房ERP在基因轉(zhuǎn)染前后無(wú)明顯變化。同時(shí),AF-EGFP組(4/7 vs.7/7)和AF-Control組(2/7vs.7/7)犬房性心律失常的誘發(fā)率明顯上升,且持續(xù)時(shí)間顯著延長(zhǎng),而AF-ACE2組犬房性心律失常的誘發(fā)率(4/7 vs.3/7)及持續(xù)時(shí)間均無(wú)明顯變化,Sham組犬僅能誘發(fā)出短暫的房性心律失常。組織學(xué)和分子生物學(xué)研究結(jié)果:HE染色可見(jiàn)實(shí)驗(yàn)犬均無(wú)明顯出血及炎癥滲出等。假手術(shù)組細(xì)胞間隙適中,纖維排列整齊;AF-Control組和AF-EGFP組心房肌纖維排列紊亂,出現(xiàn)明顯的攣縮和斷裂;而上述異常在AF-ACE2組明顯減輕,與AF-Control組和AF-EGFP組相比,轉(zhuǎn)染ACE2后心房肌纖維分布相對(duì)整齊,排列大致有序。天狼猩紅染色顯示AF-Control組和AF-EGFP組心肌間質(zhì)纖維化明顯,纖維組織增生顯著,膠原纖維分布廣泛,纖維化程度明顯強(qiáng)于Sham組和AF-ACE2組。定量分析結(jié)果表明AF-ACE2組的膠原面積明顯低于AF-Control組和AF-EGFP組(P0.0001),與Sham組無(wú)明顯差異(P=0.234)。免疫印跡技術(shù)評(píng)價(jià)RAS成員的表達(dá),結(jié)果顯示AF-Control組和AF-EGFP組AT1R蛋白的表達(dá)水平顯著高于Sham組和AF-ACE2組,而AT2R蛋白的表達(dá)水平在AF-Control組和AF-EGFP組顯著降低。Apelin和Aplnr的蛋白表達(dá)在AF-Control組和AF-EGFP組顯著降低,而過(guò)表達(dá)ACE2則顯著升高了兩者的表達(dá)水平(P0.05)。免疫印跡技術(shù)評(píng)價(jià)Rac1、Rad GTPase和Gem的表達(dá)結(jié)果顯示:AF-Control組和AF-EGFP組Rac1蛋白的表達(dá)水平顯著高于Sham組和AF-ACE2組(P0.05)。而Rad GTPase的表達(dá)在AF-ACE2組顯著升高(P0.0001),與Rad同屬于RKG家族的Gem在AF-Control組和AF-EGFP組的表達(dá)也顯著降低(P0.0001)。免疫組化方法評(píng)價(jià)Rac1和Gem所得結(jié)果與上述免疫印跡法的結(jié)果一致。免疫印跡技術(shù)評(píng)價(jià)CTGF、α-SMA和N-Cadherin的表達(dá),結(jié)果顯示三者在AF-Control組和AF-EGFP組的表達(dá)均顯著升高,而過(guò)表達(dá)ACE2則逆轉(zhuǎn)了這一趨勢(shì)。同時(shí)采用免疫組織化學(xué)熒光方法檢測(cè)α-SMA的表達(dá),結(jié)果表明α-SMA主要分布在細(xì)胞胞漿之中,在AF-Control組和AF-EGFP組中可見(jiàn)大量的綠色熒光細(xì)胞且α-SMA的表達(dá)強(qiáng)于Sham組和AF-ACE2組,與蛋白印跡的結(jié)果相一致。同時(shí),Realtime RT-PCR結(jié)果顯示c-jun、c-myc和c-fos的基因表達(dá)在AF-Control組和AF-EGFP組顯著升高,而在AF-ACE2組中過(guò)表達(dá)ACE2能降低三者的m RNA表達(dá)水平。結(jié)論:本研究結(jié)果表明:(1)過(guò)表達(dá)ACE2可以降低房顫的誘發(fā)率和縮短房顫的持續(xù)時(shí)間;(2)過(guò)表達(dá)ACE2調(diào)節(jié)心房快速起搏所致的RAS失衡,顯著下調(diào)AT1R的表達(dá),上調(diào)AT2R、Apelin和Aplnr的表達(dá);(3)過(guò)表達(dá)ACE2能調(diào)節(jié)Rac1和Rad GTPase的動(dòng)態(tài)平衡,顯著下調(diào)Rac1的表達(dá)和上調(diào)Rad GTPase、Gem的表達(dá),抑制纖維化相關(guān)因子CTGF、α-SMA和N-Cadherin的表達(dá)以及下調(diào)c-fos、c-jun和c-myc的基因表達(dá),以改善心房纖維化重構(gòu)。綜上所述,本研究結(jié)果表明心房過(guò)表達(dá)ACE2能夠通過(guò)調(diào)節(jié)心房快速起搏所致的失衡RAS軸向保護(hù)性方向移動(dòng)、上調(diào)Rad GTPase的表達(dá)同時(shí)下調(diào)Rac1的表達(dá)、抑制纖維化相關(guān)因子的表達(dá)這些機(jī)制來(lái)實(shí)現(xiàn)改善心房重構(gòu)和改良心房基質(zhì)的目的,從而達(dá)到有效降低房顫的誘發(fā)率和縮短房顫的持續(xù)時(shí)間的效果,房顫的防治得到最終獲益。
[Abstract]:Background: Atrial fibrillation (AF) is the most common and difficult to treat and relapse arrhythmia in clinic. It has become an epidemic in human cardiovascular disease. Many diseases such as ischemic, valvular, inflammatory and senile degenerative heart disease, hypertension and so on are easy to cause atrial fibrillation. However, it is present The therapeutic effect of atrial fibrillation is not satisfactory. A large number of studies have proved that the Renin angiotensin system (RAS) is activated to varying degrees in the occurrence and maintenance of atrial fibrillation. Angiotensin II (Angiotensin II, Ang II) is the most important effector of RAS, which has contractile vessels, promotes fibrosis and myocardial fertilizer. Big effect, which can be transformed into angiotensin converting enzyme 2 (Angiotensin converting enzyme 2, ACE2) into protective effects of angiotensin - (1-7) [Angiotensin- (1-7), Ang- (1-7)). Recent studies have shown that overexpression of ACE2 can antagonize the atrial remodeling effect mediated by Ang II. Atrial remodeling is the basic mechanism for atrial fibrillation and maintenance. The matrix of the conscience room is the basic link in the prevention and treatment of atrial fibrillation. Some studies have shown that Rac1 may increase the connective tissue growth factor (Connective Tissue Growth Factor, CTGF) in cardiac myocytes, N-Cadherin and Cx43 promote cardiac fibrosis and atrial remodeling; Rad (Ras Associated with) can inhibit the heart in the heart. The transcription of the cytoskeleton is regulated by the Rho/Rhokinase pathway. However, the regulatory mechanism of the dynamic balance of Rac1 and Rad GTPase in atrial fibrillation is not clear. The mechanism for overexpressing ACE2 to improve atrial fibrosis needs to be further explored. Objective: This study is to establish a canine atrial rapid pacing model and use the outer membrane of the atrial membrane to carry a ACE2 gene. The effects and molecular mechanisms of atrial overexpression of ACE2 on atrial remodeling in canine atrial rapid pacing were investigated by adenovirus method. Methods: 28 healthy adult hybrids (22 2Kg, male and female) were randomly divided into 4 groups, group Sham (sham operation group), group AF-Control (atrial rapid pacing control group), AF-EGFP group (heart) Atrial rapid pacing + smearing of Ad-EGFP adenovirus and AF-ACE2 group (atrial rapid pacing + smearing Ad-ACE2 adenovirus). In group AF-ACE2 and AF-EGFP group, the atrial outer membrane was coated with ACE2 and EGFP adenovirus respectively, and Sham group and AF-Control group were not stained with adenovirus. Except Sham group, AF-Control group, AF-EGFP group and group were all sustained atrium. After the rapid pacing (450 /min).2 weeks, the 4 dogs were performed the first thoracotomy and Electrophysiological Study (EP), and the gene smear was performed. After 3 weeks of transfection, second thoracotomy and EP examinations were performed, and then the specimens were executed, and the specimens of the atrium tissue were studied for the use of hematoxylin eosin (Hematoxylin-Eosin, HE) staining and the day. Wolf scarlet staining was used to evaluate the histopathological changes caused by rapid atrial pacing; the expression of AT1R, AT2R, Apelin and Aplnr in RAS members was evaluated by Western blot to explore the effect of ACE2 on RAS system; the expression of Rac1, Rad GTPase and Gem were evaluated by immunohistochemistry and immunoblotting techniques, and Western blot technique was applied. To evaluate the expression of CTGF, alpha -SMA and N-Cadherin, and to evaluate the expression of c-jun, c-myc and c-fos by real time fluorescence quantitative RT-PCR method, the effect of ACE2 on atrial fibrosis remodeling caused by rapid atrial pacing was investigated. Results: the results were compared with the results of electrophysiological examination in the two thoracotomy centers. In group AF-Control, group AF-EGFP and group AF-ACE2, the atrial ERP of the dogs decreased significantly and the frequency of AERP decreased significantly, while the ERP of the dog atrium in the Sham group had no significant changes before and after gene transfection. At the same time, the induced rate of atrial arrhythmia in AF-EGFP group (4/7 vs.7/7) and AF-Control group (2/7vs.7/7) was significantly increased, and the duration was significant. There was no obvious change in the induction rate (4/7 vs.3/7) and duration of atrial arrhythmia in group AF-ACE2. The dogs in group Sham could only induce transient atrial arrhythmias. Histology and molecular biology research results: HE staining showed that there was no obvious bleeding and inflammatory infiltration in the experimental dogs. The sham operation group had moderate intercellular space and fiber arrangement. The atrial fibers in group AF-Control and group AF-EGFP were arranged in disorder and showed obvious contracture and fracture, and the abnormality of the above abnormality was obviously reduced in group AF-ACE2. Compared with group AF-Control and AF-EGFP, the distribution of the fibers in the atrial muscle was relatively neatly and orderly after the transfection of ACE2. Sirius scarlet staining showed the interstitial fibrosis of the AF-Control group and the AF-EGFP group. The proliferation of the fibrous tissue was obvious, the collagen fiber was widely distributed, the fibrosis degree was stronger than the Sham group and the AF-ACE2 group. The quantitative analysis showed that the area of collagen in AF-ACE2 group was obviously lower than that of group AF-Control and AF-EGFP group (P0.0001), and there was no significant difference between group AF-ACE2 and Sham group (P=0.234). The expression of RAS members was evaluated by immunoblotting technique, and the results showed A. The expression level of AT1R protein in group F-Control and AF-EGFP group was significantly higher than that in group Sham and AF-ACE2, but the expression level of AT2R protein in AF-Control group and AF-EGFP group decreased significantly in AF-Control group and AF-EGFP group. The expression of Rac1, Rad GTPase and Gem showed that the expression level of Rac1 protein in AF-Control group and AF-EGFP group was significantly higher than that of Sham and AF-ACE2 group (P0.05). The results of Rac1 and Gem were consistent with the results of Western blot. The expression of CTGF, alpha -SMA and N-Cadherin were evaluated by Western blot technique. The results showed that the expression of three in AF-Control and AF-EGFP groups increased significantly, while the overexpression of ACE2 reversed this trend. The immunofluorescence method was used to detect the immunofluorescence. The expression of alpha -SMA showed that alpha -SMA was mainly distributed in cytoplasm. A large number of green fluorescent cells were found in group AF-Control and AF-EGFP, and the expression of alpha -SMA was stronger than that of Sham and AF-ACE2 groups. The results of Realtime RT-PCR showed c-Jun, c-myc and c-fos genes were expressed in the group of c-Jun, c-myc and c-fos. And AF-EGFP group significantly increased, and over expression of ACE2 in group AF-ACE2 could reduce the m RNA expression of three. Conclusion: (1) overexpression of ACE2 can reduce the induced rate of atrial fibrillation and shorten the duration of atrial fibrillation; (2) over expression of ACE2 regulates RAS imbalance caused by rapid atrial pacing, significantly downregulates the expression of AT1R, up AT2R, Ape The expression of Lin and Aplnr; (3) over expression of ACE2 can regulate the dynamic balance of Rac1 and Rad GTPase, significantly down regulation of the expression of Rac1 and up regulation of Rad GTPase, the expression of Gem, inhibition of fibrosis related factor CTGF, alpha -SMA and expression and down regulation and gene expression, in order to improve the remodeling of atrial fibrosis. In summary, this study The results showed that the over expression of ACE2 in the atrium was able to move the unbalanced RAS axially by regulating the atrial rapid pacing, up the expression of Rad GTPase and down regulation of the expression of Rac1 and inhibiting the expression of fibrosis related factors to improve atrial remodeling and the purpose of improving the atrial matrix, thus effectively reducing the room. The rate of fibrillation induction and the duration of atrial fibrillation are reduced, and the prevention and cure of atrial fibrillation is the ultimate benefit.

【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R541.75

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