本文選題：心肌梗死 + 心室重構(gòu)��； 參考：《武漢大學(xué)》2016年博士論文

【摘要】：背景：急性心肌梗死(acute myocardial infarction, AMI)是指因冠狀動(dòng)脈斑塊破裂或痙攣導(dǎo)致冠脈血管急性、持續(xù)性閉塞而引起心肌組織缺血缺氧導(dǎo)致心肌壞死。AMI后,在免疫炎癥因子、神經(jīng)體液紊亂、心肌缺血和心臟負(fù)荷異常等因素作用下導(dǎo)致心室重構(gòu),包括心肌細(xì)胞及細(xì)胞間質(zhì)結(jié)構(gòu)、功能和表型等異常改變。如何預(yù)防和治療AMI后心室重構(gòu)成為當(dāng)今心血管病學(xué)研究的熱點(diǎn)和主要挑戰(zhàn)。microRNAs(miRNAs)是一類約含22個(gè)核苷酸的非編碼小RNA分子,通過與靶基因mRNA的3'-UTR區(qū)結(jié)合抑制其翻譯或致其降解,在轉(zhuǎn)錄后水平上影響基因表達(dá),發(fā)揮重要生物功能。多種炎癥疾病中發(fā)現(xiàn)microRNA-155(miR-155)表達(dá)上調(diào),如類風(fēng)濕性關(guān)節(jié)炎和動(dòng)脈粥樣硬化等。AMI患者血清中miR-155的表達(dá)顯著上調(diào),并與患者1年內(nèi)的死亡風(fēng)險(xiǎn)密切相關(guān)。但是miR-155在AMI后心室重構(gòu)中的作用及其機(jī)制,特別是對(duì)心臟成纖維細(xì)胞的作用仍不清楚。本研究利用miR-155過表達(dá)和miR-155敲除小鼠,通過結(jié)扎小鼠冠狀動(dòng)脈前降支(LAD)建立AMI模型,研究miR-155對(duì)AMI后心臟功能和心室重構(gòu)的影響,并探討其潛在的作用機(jī)制。第一部分：miR-155對(duì)小鼠AMI后心臟功能及心室重構(gòu)的影響目的：探討miR-155對(duì)小鼠AMI后心臟功能及心室重構(gòu)的影響。方法：利用miR-155基因敲除(miR-155-/-)、基因過表達(dá)(miR-155+／+)及野生型(Wild Type, WT)小鼠,通過結(jié)扎LAD近端建立AMI模型,假手術(shù)組(sham)小鼠穿針不結(jié)扎。在術(shù)后第1,7和14天通過心臟超聲觀察小鼠的左心室結(jié)構(gòu)及功能改變。術(shù)后14天,通過TTC染色和Masson染色檢測小鼠心肌梗死面積、左室擴(kuò)張指數(shù)以及疤痕的厚度。免疫組化檢測小鼠心肌腦鈉肽(BNP)和心肌肌鈣蛋白I (cTnI)的表達(dá)變化。結(jié)果： (1)與sham組相比,心梗后第1,7和14天小鼠心臟功能各項(xiàng)指標(biāo)明顯受損。miR-155-/-組小鼠心梗后心功能明顯優(yōu)于WT組和miR-155+/+組小鼠。(2)TTC染色發(fā)現(xiàn)miR-1554-小鼠的梗死面積明顯小于WT和miR-155+/+小鼠。miR-155+/+小鼠的梗死面積明顯大于WT和miR-155-/-小鼠。(3) Masson染色發(fā)現(xiàn)miR-155-/-小鼠的相對(duì)瘢痕厚度明顯低于WT和miR-155+-小鼠。miR-155-/-小鼠的左室擴(kuò)張指數(shù)明顯低于WT和miR-155+/+小鼠。 (4)miR-155-/-小鼠心肌中BNP和cTnI的表達(dá)顯著低于WT和miR-155+／+小鼠。結(jié)論：miR-155加重小鼠AMI后心臟功能的惡化和心肌損傷,促進(jìn)了心梗后心室不良重塑過程。第二部分miR-155對(duì)小鼠心臟成纖維細(xì)胞膠原蛋白合成、凋亡、增殖和表型轉(zhuǎn)化的影響目的：心肌纖維化是AMI后心室重構(gòu)的重要過程。心臟成纖維細(xì)胞在心肌纖維化過程中起主導(dǎo)作用。本部分旨在探討miR-155對(duì)小鼠心臟成纖維細(xì)胞膠原蛋白合成、凋亡、增殖和表型轉(zhuǎn)化等生物行為的影響。方法：分離WT、miR-155-/-和miR-155+/+小鼠AMI 14天后的心臟成纖維細(xì)胞和心肌細(xì)胞,使用RT-PCR法檢測miR-155和腫瘤p53蛋白誘導(dǎo)核蛋白1(TP53INP1)的表達(dá)變化。轉(zhuǎn)化生長因子-β1 (TGF-β1)與乳鼠心臟成纖維細(xì)胞共培養(yǎng)24h、48h、72h后,使用RT-PCR法檢測成纖維細(xì)胞中miR-155和Ⅰ/Ⅲ型膠原蛋白mRNA及caspase-3的表達(dá)變化。利用Western blotting檢測成纖維細(xì)胞中cleaved caspase-3表達(dá)變化。利用MTT法檢測TGF-β1刺激心臟成纖維細(xì)胞后增殖情況。利用免疫熒光法檢測平滑肌肌動(dòng)蛋白-α (α-SMA)的表達(dá)。結(jié)果： (1)與sham組比較,AMI組WT小鼠心臟成纖維細(xì)胞中miR-155的表達(dá)顯著增加,而TP53INP1表達(dá)顯著降低,而心肌細(xì)胞中miR-155和TP53INP1均無明顯變化。心肌細(xì)胞和心臟成纖維細(xì)胞中TP53INP1的表達(dá)在miR-155+/+小鼠AMI后顯著下調(diào),而在miR-155-/-小鼠顯著上調(diào)。(2) TGF-β1刺激WT小鼠心臟成纖維細(xì)胞后其miR-155表達(dá)水平顯著上調(diào),且呈時(shí)間依賴性,Ⅰ/Ⅲ型膠原蛋白表達(dá)水平顯著上調(diào),其表達(dá)在miR-155+/+組更顯著,而miR-155敲除后能夠抑制TGF-β1介導(dǎo)的collagen Ⅰ/Ⅲ上調(diào)。(3)在WT小鼠心臟成纖維細(xì)胞中,TGF-β1刺激使caspase-3的mRNA表達(dá)水平及其剪切體蛋白(cleaved caspase-3)水平顯著下調(diào)。miR-155+/+組caspase-3的mRNA表達(dá)水平明顯低于野生型組,而miR-155基因敲除能夠逆轉(zhuǎn)TGF-β1介導(dǎo)的caspase3表達(dá)下調(diào)。 (4)與WT相比,miR-155過表達(dá)顯著促進(jìn)心臟成纖維細(xì)胞的增殖,而敲除miR-155后則抑制其增殖。 (5)miR-155+/+組心臟成纖維細(xì)胞α-SMA的表達(dá)水平顯著升高,而miR-155-/-組的心臟成纖維細(xì)胞α-SMA的表達(dá)水平則顯著降低。結(jié)論：小鼠AMI后心臟成纖維細(xì)胞miR-155表達(dá)顯著增加,促進(jìn)成纖維細(xì)胞的增殖和Ⅰ/Ⅲ型膠原蛋白的合成,抑制成纖維細(xì)胞凋亡,并誘導(dǎo)其向肌成纖維細(xì)胞轉(zhuǎn)化,其機(jī)制可能與抑制TP53INP1表達(dá)有關(guān)。第三部分：miR-155靶向調(diào)節(jié)TP53INP1影響心臟成纖維細(xì)胞膠原蛋白合成、凋亡、增殖和表型轉(zhuǎn)化目的：明確miR-155是否通過靶向調(diào)節(jié)TP53INP1影響心臟成纖維細(xì)胞膠原蛋白合成、凋亡、增殖和表型轉(zhuǎn)化方法：通過生物信息學(xué)預(yù)測miR-155的靶基因并用熒光素酶報(bào)告基因檢測驗(yàn)證。miR-155模擬物或抑制劑轉(zhuǎn)染乳鼠心臟成纖維細(xì)胞,檢測miR-155對(duì)心臟成纖維細(xì)胞中TP53INP1表達(dá)的影響。合成靶基因TP53INP1的小片段干擾核糖核酸(siRNA),轉(zhuǎn)染野生型或miR-1554-小鼠的心臟成纖維細(xì)胞,檢測各組心臟成纖維細(xì)胞中Ⅰ/Ⅲ型膠原蛋白和caspase-3 mRNA及蛋白表達(dá)變化,MTT法檢測心臟成纖維細(xì)胞增殖。免疫熒光檢測各組a-SMA的表達(dá)變化。結(jié)果：(1)生物信息學(xué)預(yù)測TP53INP1是miR-155的靶基因,熒光素酶報(bào)告基因?qū)嶒?yàn)顯示miR-155能與TP53INP1基因3'-UTR結(jié)合。心臟成纖維細(xì)胞中miR-155模擬物顯著抑制TP53INP1的mRNA和蛋白表達(dá)水平,而miR-155抑制劑顯著增加TP53INP1的mRNA和蛋白表達(dá)水平。(2) TP53INP1沉默后成纖維細(xì)胞合成Ⅰ/Ⅲ型膠原蛋白顯著增加,caspase-3的表達(dá)水平下降。(3)在野生型和miR-1554-的心臟成纖維細(xì)胞中,與陰性對(duì)照組相比,TP53INP1干擾后顯著促進(jìn)心臟肌成纖維細(xì)胞的增殖,心臟成纖維細(xì)胞α-SMA的表達(dá)水平顯著增加。結(jié)論：miR-155通過靶向調(diào)控TP53INP1的表達(dá),促進(jìn)心臟成纖維細(xì)胞的增殖、膠原合成和表型轉(zhuǎn)化,并抑制成纖維細(xì)胞凋亡,與心梗后心肌纖維化有關(guān)。
[Abstract]:Background: acute myocardial infarction (acute myocardial infarction, AMI) refers to the causes of acute myocardial infarction caused by coronary artery plaque rupture or spasm resulting in myocardial ischemia and hypoxia caused by myocardial ischemia and hypoxia caused by persistent occlusion of the coronary artery, and it leads to immune inflammatory factors, neurohumoral disorders, myocardial ischemia, and abnormal cardiac load. Ventricular remodeling, including abnormal changes in cardiac myocytes and interstitial structures, functions and phenotypes. How to prevent and treat ventricular remodeling after AMI has become a hot and major challenge in current cardiovascular disease research.MicroRNAs (miRNAs) is a class of non coded small RNA molecules containing approximately 22 nucleotides, binding to the 3'-UTR region of the target gene mRNA. MicroRNA-155 (miR-155) expression up-regulated in a variety of inflammatory diseases, such as rheumatoid arthritis and atherosclerosis, the expression of miR-155 in the serum of.AMI patients, such as rheumatoid arthritis and atherosclerosis, is up significantly up, and is closely related to the risk of death within 1 years of the patient. However, the role of miR-155 in ventricular remodeling after AMI and its mechanism, especially for cardiac fibroblasts, is still unclear. This study used miR-155 overexpression and miR-155 knockout mice to establish AMI model by ligating the anterior descending branch of coronary artery (LAD) in mice to study the effect of miR-155 on cardiac function and ventricular remodeling after AMI, and to explore the effect of miR-155 on cardiac function and ventricular remodeling. Potential mechanism of action. Part 1: the effect of miR-155 on cardiac function and ventricular remodeling in mice after AMI: To explore the effect of miR-155 on cardiac function and ventricular remodeling in mice after AMI. Methods: using miR-155 gene knockout (miR-155-/-), gene overexpression (miR-155+ / +) and wild type (Wild Type, WT) mice, by ligation LAD near The AMI model was established at the end of the group, and the sham operation group (sham) was not ligation. The left ventricular structure and function of the mice were observed by echocardiography at 1,7 and 14 days after the operation. The infarct area, the left ventricular dilatation index and the thickness of the scar were detected by TTC staining and Masson staining on the 14 day after operation. Changes in expression of BNP and cardiac troponin I (cTnI). Results: (1) compared with group sham, the cardiac function indexes of mice after 1,7 and 14 days after myocardial infarction were significantly impaired in.MiR-155-/- group after myocardial infarction. (2) TTC staining found that the infarct area of miR-1554- mice was significantly smaller than WT and miR-155+/+. The infarct area of mouse.MiR-155+/+ mice was significantly greater than that of WT and miR-155-/- mice. (3) Masson staining showed that the relative scar thickness of miR-155-/- mice was significantly lower than that of WT and miR-155+- mice, and the left ventricular dilatation index of.MiR-155-/- mice was significantly lower than that of WT and miR-155+/+ mice. (4) the expression of BNP in the miR-155- / - mouse myocardium was significantly lower than that of the miR-155+/+ mice. And miR-155+ / + mice. Conclusion: miR-155 aggravates the deterioration of cardiac function and myocardial injury after AMI in mice, promotes the process of ventricular remodeling after myocardial infarction. Second the effect of part miR-155 on collagen synthesis, apoptosis, proliferation and phenotypic transformation of cardiac fibroblasts in mice: myocardial fibrosis is an important part of ventricular remodeling after AMI Cardiac fibroblasts play a leading role in the process of myocardial fibrosis. This part aims to explore the effects of miR-155 on the biological behavior of collagen synthesis, apoptosis, proliferation and phenotypic transformation of cardiac fibroblasts in mice. Methods: isolation of cardiac fibroblasts and cardiac myocytes from WT, miR-155-/- and miR-155+/+ mice for 14 days after AMI. The expression of miR-155 and tumor p53 protein induced nucleoprotein 1 (TP53INP1) expression was detected by RT-PCR. TGF - beta 1 (TGF- beta 1) was co cultured with 24h, 48h, and 72h in rat heart fibroblasts. The expression of mRNA and Caspase-3 in fibroblasts was detected by RT-PCR method. The expression of cleaved caspase-3 in fibroblasts was detected. The proliferation of TGF- beta 1 stimulated cardiac fibroblasts was detected by MTT method. The expression of smooth muscle actin - alpha (alpha -SMA) was detected by immunofluorescence. Results: (1) the expression of miR-155 in cardiac fibroblasts of WT mice of AMI group increased significantly compared with sham group, and TP53INP in WT mice of AMI group increased significantly, and TP53INP The expression of 1 was significantly decreased, but there was no significant change in miR-155 and TP53INP1 in cardiac myocytes. The expression of TP53INP1 in cardiac myocytes and cardiac fibroblasts decreased significantly after AMI in miR-155+/+ mice, and in miR-155-/- mice significantly up. (2) TGF- beta 1 stimulated the miR-155 expression level of WT mice after cardiac fibroblasts. Inter dependence, the expression level of type I / III collagen was significantly up-regulated, and its expression was more significant in miR-155+/+ group, while miR-155 knockout could inhibit the up regulation of collagen I / III mediated by TGF- beta 1. (3) in WT mouse cardiac fibroblasts, TGF- beta 1 stimulated the level of Caspase-3 mRNA expression and the level of cleaved caspase-3 (cleaved caspase-3). The mRNA expression level of Caspase-3 in.MiR-155+/+ group was significantly lower than that in the wild type group, while miR-155 gene knockout could reverse the TGF- beta 1 mediated Caspase3 expression. (4) over expression of miR-155 significantly promoted the proliferation of cardiac fibroblasts compared with WT, and the proliferation was inhibited after miR-155. (5) cardiac fibroblasts in the miR-155+/+ group The expression level of alpha -SMA increased significantly, while the expression level of alpha -SMA in cardiac fibroblasts in group miR-155-/- decreased significantly. Conclusion: the expression of miR-155 in cardiac fibroblasts in mice after AMI was significantly increased, promoting the proliferation of fibroblasts and the synthesis of type I / III collagen, inhibiting the apoptosis of fibroblasts and inducing it to myofibroblast. Cell transformation, its mechanism may be related to the inhibition of TP53INP1 expression. Third part: miR-155 targeting regulation of TP53INP1 affects the collagen synthesis, apoptosis, proliferation and phenotypic transformation of cardiac fibroblasts: to determine whether miR-155 affects collagen synthesis, apoptosis, proliferation and phenotypic transformation of cardiac fibroblasts through targeting regulation of TP53INP1 Methods: using bioinformatics to predict the target gene of miR-155 and using luciferase reporter gene detection to verify the effect of miR-155 on the expression of TP53INP1 in cardiac fibroblasts, the effect of the.MiR-155 analog or inhibitor on the expression of TP53INP1 in the cardiac fibroblasts. The small fragment interfering ribonucleic acid (siRNA) of the target gene TP53INP1, and the transfection field The expression of type I / III collagen and caspase-3 mRNA and protein in cardiac fibroblasts were detected in the cardiac fibroblasts of miR-1554- mice. The proliferation of cardiac fibroblasts was detected by MTT method. The expression of a-SMA in each group was detected by immunofluorescence. Results: (1) the prediction of TP53INP1 was the target gene of miR-155, and the fluorescence of TP53INP1 was the target gene of miR-155. MiR-155 can bind to the TP53INP1 gene 3'-UTR. MiR-155 mimics in cardiac fibroblasts significantly inhibit the mRNA and protein expression level of TP53INP1, while miR-155 inhibitors significantly increase the mRNA and protein expression level of TP53INP1. (2) TP53INP1 after silencing of TP53INP1, the synthesis of type I / III collagen in fibroblasts The expression level of Caspase-3 decreased. (3) in the wild and miR-1554- cardiac fibroblasts, compared with the negative control group, the TP53INP1 interference significantly promoted the proliferation of cardiac myofibroblast and the expression level of the alpha -SMA in the cardiac fibroblasts increased significantly. Conclusion: miR-155 promotes the expression of TP53INP1 by targeting the target and promotes the expression of miR-155. The proliferation, collagen synthesis and phenotypic transformation of cardiac fibroblasts, and the inhibition of apoptosis of fibroblasts, are related to myocardial fibrosis after myocardial infarction.

【學(xué)位授予單位】：武漢大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R542.22

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