發(fā)布時間：2018-07-02 14:44

  本文選題：心肌肥厚模型 + 肥厚標志基因�。� 參考：《安徽醫(yī)科大學》2016年博士論文

【摘要】：背景肥厚型心肌病(hypertrophic cardiomyopathy, HCM)是以心肌肥厚為特征,心肌細胞肥大和肌纖維排列紊亂等是其典型表現(xiàn)。目前認為HCM的病因多與遺傳有關(guān),是一種常染色體顯性遺傳病。胚胎基因p-肌球蛋白重鏈(β-myosin heavy chain,β-MHC)、腦利尿鈉肽(brain natriuretic peptide, BNP)和心房利尿鈉肽(atrial natriuretic peptide, ANP)等基因重新表達被認為是心臟肥厚的分子標志,檢測這些基因的表達不僅可以肯定心臟肥厚的存在,而且可以判斷肥厚的程度及預(yù)后。當前基因芯片技術(shù)顯示,不同心肌肥厚模型引起基因表達水平的方向、數(shù)目和種類各不相同,如利用動-靜脈瘺和去甲腎上腺素制備的心肌肥厚模型中,其發(fā)生變化的34個基因中有14個調(diào)節(jié)方向相反。腎上腹主動脈縮窄(renal abdominal aortic coarctation, AAC)、動靜脈瘺(arteriovenous fistula, AVF)和異丙腎上腺素(isoproterenol, ISO)法制備的心肌肥厚模型,都是經(jīng)典的且被國內(nèi)外研究者廣泛認可的模型,但這三種不同心肌肥厚模型間肥厚性標志基因ANP、BNP和β-MHC表達有無差異尚不清楚。因此采用AAC、AVF和ISO法制備心肌肥厚小鼠模型,檢測ANP、BNP和β-MHC的表達差異,以期優(yōu)選出心肌肥厚標志基因表達明顯的造模方法。動物造模,離不開動物品系的選擇,不同品系動物,采用相同的方法造模亦存在差異,這些差異多數(shù)是由不同的遺傳背景所造成的。遺傳背景不同,導致特定的基因表達水平亦不同,但目前以與人類遺傳密切相關(guān)的HCM肥厚分子標志(ANP、BNP和β-MHC)為靶標,對不同品系小鼠HCM心肌肥厚模型進行篩選將產(chǎn)生何種影響尚不明確,因此比較不同品系小鼠心肌肥厚模型間ANP、BNP和β-MHC的表達差異性具有一定的必要性。目前治療HCM主要方法有藥物和手術(shù)治療等。2015年版藥典記載的雙丹口服液,功能主治為養(yǎng)心活血、化瘀止痛。本課題組前期研究結(jié)果顯示,雙丹提取物中兩種主要有效成分(丹酚酸B和丹皮酚組合的新復方,簡稱SP)具有協(xié)同作用,并在心肌缺血模型中觀察到SP具有明顯的舒張血管功能和對動-靜脈瘺心肌肥厚模型小鼠具有一定的防治作用,但其防治作用與ANP、BNP和P-MHC的表達是否相關(guān)及SP作用機制尚未明確。據(jù)報道心肌肥厚與纖維化密切相關(guān)且伴隨著TGF-β1表達上調(diào),通常Smad蛋白被認為是TGF-β1信號通路下游介質(zhì)之一,其中Smad2、3可促進TGF-β1刺激信號從細胞質(zhì)向細胞核傳導,而當前認為TGF-β1信號轉(zhuǎn)導可以被Smad7抑制,Smad7可阻斷信號轉(zhuǎn)導,抑制相關(guān)靶基因的轉(zhuǎn)錄和蛋白表達,這主要是由于TGF-β1型受體被配體激活后,Smad7與激活型Smad可與其競爭性結(jié)合。因此本研究亦將探索SP對心肌肥厚小鼠ANF、BNP和β-MHC的表達及TGF-β/Smad信號通路的影響。目的1.從三種造模方法AAC、AVF和ISO中優(yōu)選心肌肥厚標志性基因ANP、BNP和β-MHC表達明顯的造模方式；2.從四種不同品系BALB/c、C57BL/6、ICR和KM小鼠心肌肥厚模型中,優(yōu)選心肌肥厚標志性基因ANP、BNP和β-MHC表達明顯的小鼠品系；3.在優(yōu)選、制備理想心肌肥厚模型的基礎(chǔ)上,探索SP對其模型小鼠ANP、BNP和β-MHC表達及TGF-β/Smad信號通路的影響。方法1.將C57BL/6小鼠隨機分為對照組和模型組,造模組分別采用AVF、AAC和ISO法制備心肌肥厚模型；再取KM、ICR、C57BL/6和BALB/c四個品系小鼠分別隨機分為對照組和模型組,后者均采用前面實驗結(jié)果制備心肌肥厚模型。上述小鼠均在4周后,稱取體重(body weight, BW),頸椎脫臼處死,稱量心臟重量(heartweight, HW)和左室重量(left ventricular weight, LVW),計算心臟指數(shù)(HW/BW)和左心室指數(shù)(LVW/BW).一部分心臟組織標本分離后快速沖洗、分裝,并于液氮凍存,以備后續(xù)采用qRT-PCR檢測；另一部分心臟組織用生理鹽水漂洗,10%甲醛固定24h后,經(jīng)沖洗、脫水、硬化、透明、浸滲等步驟后進行石蠟包埋、切片、蘇木精-伊紅(hematoxylin-eosin, HE)染色、攝片和組織芯片制作、免疫組織化學法觀察ANP、BNP和β-MHC蛋白表達。2.將上述實驗優(yōu)選的小鼠品系,隨機分為對照組和造模組,后者采用前面實驗優(yōu)選的方法制備,2周后將造模組隨機分為：模型,陽性藥和SP大、中、小劑量組,并開始灌胃給藥至第4周末。陽性藥組每天按35mg/kg給予卡托普利片,SP大、中、小劑量組分別每天按60,30和15mg/kg給予SP溶液,對照組和模型組給予等容量溶媒。末次給藥后2小時,稱取各小鼠BW,頸椎脫臼處死,稱量HW和LVW,計算HW/BW和LVW/BW。一部心臟組織分裝凍存,用于qRT-PCR和Western blot檢測；另一部分心臟組織HE染色、攝片和組織芯片制作、免疫組織化學法觀察ANP、BNP和β-MHC蛋白表達。結(jié)果1.不同方法誘導心肌肥厚模型小鼠間ANP、BNP和β-MHC的表達差異采用AAC、AVF和ISO法制備的心肌肥厚小鼠心臟肥厚指數(shù)HW/BW、 LVW/BW顯著增加,在高倍鏡下,可見心肌細胞肥大、排列稀疏和間質(zhì)纖維化,提示采用AAC、AVF和ISO法誘導小鼠心肌肥厚模型是成功的；與AAC法比較,ISO組HW/BW、LVW/BW和AVF組HW/BW明顯減輕,AVF和ISO組小鼠心肌室壁增厚、心室腔狹窄亦較輕,提示采用AAC法制備小鼠心肌肥厚模型產(chǎn)生的心肌肥厚程度要優(yōu)于AVF和ISO法。采用AAC和AVF法制備的心肌肥厚小鼠心臟左心室ANP、BNP和β-MHC mRNA轉(zhuǎn)錄和蛋白表達水平均明顯增加,同樣ISO法小鼠ANP和BNP mRNA轉(zhuǎn)錄和蛋白表達水平亦顯著增加,但β-MHC mRNA轉(zhuǎn)錄和蛋白表達水平僅有增加趨勢；將三種方法AAC、AVF和ISO制備的心肌肥厚模型進行相互比較,顯示AAC法小鼠左心室ANE、BNP和β-MHC mRNA轉(zhuǎn)錄和蛋白表達水平增加最明顯,提示采用AAC法上調(diào)心肌肥厚模型小鼠左心室ANP、BNP和β-MHC mRNA轉(zhuǎn)錄和蛋白水平要優(yōu)于AVF和ISO法。2.不同品系小鼠心肌肥厚模型ANP、BNP和P-MHC的表達差異采用四個品系小鼠C57BL/6、BALB/c、 KM和ICR制備心肌肥厚模型,其中C57BL/6、BALB/c、KM小鼠心臟肥厚指數(shù)HW/BW、LVW/BW顯著增加,ICR小鼠HW/BW和LVW/BW僅有增加的趨勢,HE染色顯示四個品系小鼠心肌細胞肥大,部分肌纖維斷裂,細胞間隙增加,提示采用C57BL/6、KM、BALB/c小鼠制備心肌肥厚模型是成功的,ICR小鼠不夠理想；將四個品系小鼠C57BL/6、 BALB/c、KM和ICR制備的心肌肥厚模型進行相互比較,顯示C57BL/6小鼠心臟肥厚指數(shù)HW/BW和LVW/BW增加最明顯,其次為KM小鼠,提示采用C57BL/6小鼠制備小鼠心肌肥厚模型產(chǎn)生的心肌肥厚程度要優(yōu)于BALB/c、KM和ICR。采用四個品系小鼠C57BL/6、BALB/c、KM和ICR制備心肌肥厚模型,其中C57BL/6、KM小鼠心臟左心室ANP、BNP和β-MHC mRNA轉(zhuǎn)錄和蛋白表達水平均明顯增加,而BALB/c小鼠BNP和ICR小鼠ANP、BNP mRNA轉(zhuǎn)錄和蛋白水平僅有增加趨勢；將四個品系小鼠C57BL/6、BALB/c、KM和ICR制備的心肌肥厚模型進行相互比較,顯示C57BL/6小鼠左心室ANP、BNP和β-MHC mRNA轉(zhuǎn)錄和蛋白表達水平增加最明顯,提示采用C57BL/6小鼠制備的心肌肥厚模型ANP. BNP和β-MHC mRNA轉(zhuǎn)錄和蛋白水平要優(yōu)于BALB/c、KM和ICR小鼠。3.SP對心肌肥厚小鼠ANP、BNP和β-MHC表達及TGF-β/Smad信號通路影響采用AAC法制備C57BL/6小鼠心肌肥厚模型,顯示造模小鼠心臟肥厚指數(shù)HW/BW和LVW/BW明顯增加,心臟體積增加,心肌細胞肥大,部分肌纖維斷裂,細胞間隙增加,提示本次實驗的模型是成功的；CAP和SP組大、中劑量均可使模型小鼠肥厚指數(shù)HW/BW和LVW/BW顯著降低,心臟體積減小,肌纖維斷裂程度減輕,細胞間隙變小,且CAP和SP比較無顯著差異,提示SP可明顯降低AAC法致心肌肥厚模型C57BL/6小鼠心臟肥厚指數(shù)HW/BW、LVW/BW和心肌病理性損傷,其作用強度與卡托普利片相當。采用AAC法制備C57BL/6小鼠心肌肥厚模型,顯示造模小鼠心臟左心室ANP、BNP和β-MHC mRNA轉(zhuǎn)錄和蛋白表達水平明顯增強；CAP和SP組大、中劑量均可使造模小鼠左心室ANP、BNP和β-MHC mRNA轉(zhuǎn)錄和蛋白表達水平明顯降低,且CAP和SP比較無顯著差異,提示SP可明顯降低AAC法致心肌肥厚模型C57BL/6小鼠左心室ANP、BNP和β-MHC mRNA轉(zhuǎn)錄和蛋白表達水平,其作用強度與卡托普利片相當。采用AAC法制備C57BL/6小鼠心肌肥厚模型,顯示造模小鼠心臟左心室TGF-p1. Smad2和Smad3 mRNA轉(zhuǎn)錄水平顯著增加,但Smad7 mRNA轉(zhuǎn)錄水平無明顯差異；CAP和SP組大、中劑量均可顯著下調(diào)造模小鼠左心室TGF-β1、Smad2、 Smad3 mRNA轉(zhuǎn)錄和Smad3蛋白表達水平,明顯上調(diào)Smad7 mRNA轉(zhuǎn)錄和蛋白表達水平,提示SP對心肌肥厚的防治作用機制可能與調(diào)控TGF-β/Smad信號通路有關(guān)。結(jié)論1.AVF、AAC和ISO三種方法制備小鼠心肌肥厚模型,以心肌肥厚小鼠左心室ANP、BNP和β-MHC表達為篩選條件,結(jié)果表明以AAC法制備的小鼠心肌肥厚模型最理想；2.心肌肥厚小鼠左心室ANP、BNP和β-MHC表達為篩選條件,AAC法制備C57BL/6、BALB/c、KM和ICR四種不同品系小鼠心肌肥厚模型中,以C57BL/6品系小鼠模型最理想；3.SP明顯抑制AAC法誘導的C57BL/6小鼠的心肌肥厚,抑制心肌肥厚小鼠的ANP、BNP和β-MHC的表達；4.SP抑制小鼠心肌肥厚的作用機制可能與調(diào)控TGF-β/Smad信號通路有關(guān)。
[Abstract]:Background hypertrophic cardiomyopathy (hypertrophic cardiomyopathy, HCM) is characterized by cardiac hypertrophy, cardiomyocyte hypertrophy and disorder of muscle fiber arrangement. It is believed that the etiology of HCM is mostly associated with heredity, and is an autosomal dominant genetic disease. The embryo gene p- myosin heavy chain (beta -myosin heavy chain, beta -MHC), brain benefit The reexpression of brain natriuretic peptide (BNP) and atrial natriuretic peptide (atrial natriuretic peptide, ANP) is considered as a molecular marker of cardiac hypertrophy. The expression of these genes can not only confirm the existence of cardiac hypertrophy, but also determine the degree and prognosis of hypertrophy. Current gene chip technology shows that The number and type of gene expression level in different cardiac hypertrophy models are different. For example, 14 of the 34 genes in the 34 genes that have changed by using arteriovenous fistula and norepinephrine have the opposite direction. The upper abdominal aorta coarctation (renal abdominal aortic coarctation, AAC), and arteriovenous fistula (a) The model of cardiac hypertrophy prepared by rteriovenous fistula, AVF) and isoproterenol (isoproterenol, ISO) method is classic and widely recognized by researchers at home and abroad. However, there is no clear difference between these three different hypertrophy models of hypertrophy gene ANP, BNP and beta -MHC. Therefore, AAC, AVF and ISO are used. The difference of expression of ANP, BNP and beta -MHC was detected in the model of myocardial hypertrophy, in order to optimize the modeling method for the expression of cardiac hypertrophy marker gene. Animal model, the selection of animal strains, different strains of animals, and the same methods were also different, most of these differences were caused by different genetic background. The genetic background is different and the specific gene expression level is different, but at present, the HCM hypertrophy molecular markers (ANP, BNP and beta -MHC) which are closely related to human heredity are the targets. The effect of screening on the HCM myocardial hypertrophy model of different strains of mice is not clear. Therefore, ANP, BNP between different strains of murine myocardial hypertrophy model is compared. The difference between the expression of HCM and beta -MHC is necessary. At present, the main methods for the treatment of -MHC are double Dan oral liquid recorded in the Pharmacopoeia of medicine and operation, and the function is to nourish heart and promote blood circulation and relieve the pain and relieve pain. The new compound, called SP, has synergistic effect. In the myocardial ischemia model, SP has obvious vasodilatation function and has some preventive effect on the model mice with arteriovenous fistula myocardial hypertrophy, but its effect is related to the expression of ANP, BNP and P-MHC, and the mechanism of SP is not clear. It is reported that the myocardial hypertrophy and fibrinolysis is reported. It is closely related and up-regulated with the expression of TGF- beta 1. Generally, Smad protein is considered to be one of the downstream mediators of the TGF- beta 1 signaling pathway, in which Smad2,3 can promote the conduction of TGF- beta 1 stimulation signal from the cytoplasm to the nucleus. At present, it is believed that TGF- beta 1 signal transduction can be suppressed by Smad7, Smad7 can block signal transduction and inhibit the transfer of related target genes. The transcription and protein expression is mainly due to the competitive binding of Smad7 and activator Smad after the TGF- beta 1 receptor is activated by the ligand. Therefore, this study will also explore the effect of SP on the expression of ANF, BNP and beta -MHC and the TGF- beta /Smad signaling pathway in myocardial hypertrophy mice. Objective 1. the markers of cardiac hypertrophy in AAC, AVF and ISO were selected from three modeling methods. The expression of sex genes ANP, BNP and beta -MHC expressed a significant model. 2. from the four different strains of BALB/c, C57BL/6, ICR and KM mouse cardiac hypertrophy, the selection of cardiac hypertrophy marker gene ANP, BNP and beta -MHC expressed obviously in mice; 3. on the basis of optimal selection of ideal myocardial fat thickness model, SP on its model mice ANP The expression of beta -MHC and the effect of TGF- beta /Smad signaling pathway. Method 1. C57BL/6 mice were randomly divided into control group and model group. The model of myocardial hypertrophy was prepared by AVF, AAC and ISO, and KM, ICR, C57BL/6 and BALB/c were randomly divided into the control group and the model group, the latter were prepared by the previous experimental results. The model of muscle hypertrophy. After 4 weeks, the mice were weighed (body weight, BW), the cervical dislocations were killed, the weight of the heart (heartweight, HW) and the left ventricular weight (left ventricular weight, LVW) were weighed, and the cardiac index (HW/BW) and the left ventricular index (LVW/BW) were calculated. QRT-PCR test was used for follow-up; the other part of the heart tissue was rinsed with saline and 10% formaldehyde was fixed for 24h. After washing, dehydration, hardened, transparent, impregnated and other steps, paraffin was embedded, sliced, hematoxylin eosin (hematoxylin-eosin, HE) staining, film and tissue chips were made, and ANP, BNP and beta -MHC eggs were observed by immunohistochemistry. The white expression.2. was divided into the control group and the model group randomly. The latter was prepared by the preferred method of the previous experiment. After 2 weeks, the model was randomly divided into the model, the positive drug and the SP large, medium, small dose group, and began to fill the stomach for the fourth weekend. The positive drug group was given Captopril Tablets, SP, medium every day. The small dose groups were given SP solution by 60,30 and 15mg/kg each day respectively. The control group and the model group were given equal volume solvent. 2 hours after the last administration, the mice were given BW, the cervical dislocations were killed, the HW and LVW were weighed, and the HW/BW and LVW/BW. a cardiac tissue was frozen, used for qRT-PCR and Western blot detection; the other part of the heart tissue was stained HE, The expression of ANP, BNP and beta -MHC protein was observed by immunohistochemical method. Results 1. different methods induced ANP, BNP and -MHC expression in the model mice of myocardial hypertrophy using AAC, AVF and ISO method for cardiac hypertrophy of cardiac hypertrophy index HW/BW, LVW /BW increased significantly. Under high magnification, myocardial cell fertilizer was found. Large, arranged sparsely and interstitial fibrosis, suggesting that the AAC, AVF and ISO induced murine myocardial hypertrophy model was successful. Compared with the AAC method, HW/BW, LVW/BW and AVF groups in the ISO group were significantly reduced, the myocardium wall of the AVF and ISO group was thickened and the ventricular cavity narrower was lighter, suggesting that the AAC method was used to prepare the myocardial fertilizer produced by the murine myocardial hypertrophy model. The levels of ANP, BNP and beta -MHC mRNA in cardiac hypertrophy mice were significantly higher than those of AVF and ISO. The transcriptional and protein expression levels of ANP and BNP mRNA in ISO mice were also increased significantly. However, the level of the transcription and protein expression of the ANP and BNP mRNA was also increased, but the level of the transcription and protein expression was only increased. Three The comparison of the myocardial hypertrophy models prepared by AAC, AVF and ISO showed that the transcriptional and protein expression levels of ANE, BNP and beta -MHC mRNA in the AAC mice were most obvious, suggesting that the AAC method was used to increase the left ventricular ANP, BNP and beta -MHC transcription and protein levels were smaller than those of the AAC. The difference in expression of ANP, BNP and P-MHC in the rat cardiac hypertrophy model was made by four strains of mice, C57BL/6, BALB/c, KM and ICR to prepare the model of myocardial hypertrophy. In C57BL/6, BALB/c, KM mice, the cardiac hypertrophy index was HW/BW, LVW/BW significantly increased. Muscle fiber breakage and intercellular space increased, suggesting that the C57BL/6, KM, BALB/c mice were successful in preparing the myocardial hypertrophy model, and ICR mice were not ideal. The myocardial hypertrophy model of four strains of mice, C57BL/6, BALB/c, KM and ICR, was compared with each other, showing that the increase of the cardiac hypertrophy index HW/BW and LVW/BW was the most obvious in the C57BL/6 rat, followed by K. M mice showed that the degree of myocardial hypertrophy produced by C57BL/6 mice was better than that of BALB/c. KM and ICR. used four strains of mice C57BL/6, BALB/c, KM and ICR to prepare the model of myocardial hypertrophy. C57BL/6, KM mouse heart left ventricular ANP, and beta transcription and protein expression levels were significantly increased. The transcriptional and protein levels of ANP and BNP mRNA in mice BNP and ICR only increased, and the myocardial hypertrophy model of C57BL/6, BALB/c, KM and ICR in four strains of mice was compared, showing the ANP left ventricle of C57BL/6 mice, the most obvious increase in the transcription and protein expression level of BNP and beta, suggesting the use of the myocardium prepared by the mice. The transcriptional and protein levels of the hypertrophic model ANP. BNP and beta -MHC mRNA were superior to those of BALB/c, KM and ICR mouse.3.SP on the ANP, BNP and beta -MHC expression and the effect of TGF- beta signaling pathway on the myocardial hypertrophy model of mice. Myocardial hypertrophy, partial muscle fiber breakage, and intercellular space increased, suggesting that the model of this experiment was successful. CAP and SP groups were large, medium dose could reduce the hypertrophy index HW/BW and LVW/BW significantly, reduce the volume of heart, reduce the degree of muscle fiber rupture, and reduce the gap between the cells, and the CAP and SP have no significant difference, suggesting SP can be clear. The cardiac hypertrophy model of C57BL/6 mice was significantly reduced by the AAC method. The cardiac hypertrophy index (HW/BW, LVW/BW and myocardial pathological damage) were similar to that of Captopril Tablets. The AAC method was used to prepare the C57BL/6 mouse cardiac hypertrophy model, which showed that the transcriptional and protein expression levels of ANP, BNP and beta -MHC mRNA in the left ventricle of the left heart of the mice were obviously enhanced; CAP and SP. The level of ANP, BNP and beta -MHC mRNA in the left ventricle of the model mice decreased significantly, and there was no significant difference between CAP and SP, suggesting that SP could significantly reduce the level of ANP, BNP and beta -MHC transcription and egg white expression in the C57BL/6 mouse model C57BL/6 induced by AAC method, and the effect intensity was with the Captopril Tablets phase. The TGF-p1. Smad2 and Smad3 mRNA transcriptional levels in the left ventricle of the mice were significantly increased by AAC method, but there was no significant difference in the transcriptional level of the Smad7 mRNA in the left ventricle of the mice. The CAP and SP groups were large, and the middle dose of the mice could significantly reduce the TGF- beta 1 in the left ventricle of the mice. Level, obviously up regulation of Smad7 mRNA transcriptional and protein expression level, suggesting that the mechanism of SP's prevention and control of myocardial hypertrophy may be related to the regulation of TGF- beta /Smad signaling pathway. Conclusion 1.AVF, AAC and ISO have three methods of preparation of the model of myocardial hypertrophy in mice, and the expression of ANP, BNP and beta -MHC in the left ventricle of the cardiac hypertrophic mice is selected as the screening condition, and the results show that the AAC method is used. The model of ANP, BNP and beta -MHC in the left ventricle of the 2. hypertrophic mice was selected as the screening condition. The AAC method was used to prepare the C57BL/6, BALB/c, KM and ICR mice model of myocardial hypertrophy, and the C57BL/6 strain mouse model was the best. 3.SP obviously inhibited the cardiac hypertrophy and inhibition of the myocardium in C57BL/6 mice induced by AAC method. The expression of ANP, BNP and beta -MHC in muscle hypertrophic mice; the mechanism of 4.SP inhibiting myocardial hypertrophy may be related to the regulation of TGF- /Smad signaling pathway.
【學位授予單位】：安徽醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R542.2;R-332

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