發(fā)布時間：2018-05-04 08:25

  本文選題：脂聯(lián)素 + 脂聯(lián)素基因敲擊小鼠��； 參考：《山西醫(yī)科大學》2017年博士論文

【摘要】：當前,在全世界范圍內(nèi),心血管疾病的發(fā)病率和死亡率均位于前幾位,對人們的身心健康有著重大威脅。目前我國罹患心血管病者約2.3億人,其中約300萬人因該病死亡。在心腦血管病變中動脈粥樣硬化(Atherosclerosis,AS)為關鍵的病理基礎,以膽固醇代謝異常為主的脂質(zhì)代謝紊亂是重要的致病因素;該疾病最主要的病理特點是巨噬細胞能清除高水平的脂質(zhì)產(chǎn)生泡沫細胞�；�于以上背景,研究者們熱衷于探討動脈粥樣硬化病變的發(fā)生發(fā)展機制、怎樣避免形成泡沫細胞。膽固醇逆轉(zhuǎn)運(Reverse Cholesterol ransport,RCT)指的是把細胞中含有的游離性膽固醇向胞外轉(zhuǎn)移,并聚集至肝臟,最終排出機體;RCT全過程包括下列各步驟:最初外周細胞內(nèi)含有大量膽固醇經(jīng)轉(zhuǎn)運蛋白(如ABCA1和ABCG1等)的介導進而結(jié)合于載脂蛋白,生成成熟狀態(tài)的HDL,再隨著血液系統(tǒng)聚集到肝臟,最后排出機體。ATP結(jié)合盒轉(zhuǎn)運子(Binding Cassette Transporter,ABC)屬于當前存在的數(shù)量最多的膜轉(zhuǎn)運家族。其中ATP三磷酸腺苷結(jié)合盒轉(zhuǎn)運子A1(ABCA1)是轉(zhuǎn)運時功能最突出的轉(zhuǎn)運蛋白,有助于細胞排出膽固醇。在ABCA1轉(zhuǎn)運蛋白的作用下脂質(zhì)可發(fā)生外流,再結(jié)合于apoA-I,進而產(chǎn)生一定水平的磷脂-apoA-I復合物,并且能夠酯化細胞外游離狀態(tài)的膽固醇,最終可生成成熟狀態(tài)的HDL,隨著血液系統(tǒng)聚集在肝臟中,進而能夠被肝臟所利用而生成膽汁酸鹽,和糞便排出體外[1-3]。所以,提升RCT水平有助于防止AS病變。相關的研究結(jié)果表明,高密度脂蛋白(High Density Lipoprotein Cholesterol,HDL-C)數(shù)量與機體發(fā)生動脈粥樣硬化的可能性呈顯著的負相關關系。HDL-C拮抗動脈粥樣硬化的主要機制在于介導RCT過程。其中RCT能將外周組織內(nèi)含有的大量膽固醇通過HDL-C轉(zhuǎn)運到肝臟以膽汁酸的形式排出體外,是目前相關領域研究者們公認的抗動脈粥樣硬化的關鍵機制。在RCT中ABCA1有利于細胞中磷脂、膽固醇向HDL-C前體apoA-I轉(zhuǎn)運,形成新生HDL-C,進而啟動RCT,所以ABCA1在RCT和HDL-C新生成中起著極其重要的起始限速作用。所以能否通過調(diào)節(jié)ABCA1蛋白的表達而達到促進膽固醇逆轉(zhuǎn)運成為廣受關注的抗動脈粥樣硬化的靶點。脂聯(lián)素(Adiponectin)主要來源于脂肪細胞,能夠發(fā)揮胰島素抵抗、抗動脈粥樣硬化及抗炎等作用。研究表明:在肥胖、高血壓、糖尿病、心肌受損、動脈粥樣硬化等病人血清內(nèi)具有較低水平的脂聯(lián)素。并且,很多臨床試驗結(jié)果顯示脂聯(lián)素濃度明顯降低與高血壓、血管內(nèi)皮受損、冠心病及心肌梗死等病變的發(fā)生發(fā)展存在緊密的聯(lián)系[4]。在發(fā)生AS疾病的過程中,脂聯(lián)素能夠?qū)ρ�管平滑肌細胞的分化、繁殖進行抑制,并避免巨噬細胞不斷轉(zhuǎn)化為泡沫細胞,使脂聯(lián)素在內(nèi)皮細胞中發(fā)揮抗AS功效。脂聯(lián)素對巨噬細胞膽固醇逆轉(zhuǎn)運的影響及其機制在\在冠狀動脈粥樣硬化AS早期內(nèi)皮細胞可被炎癥細胞激活在血管壁上沉積并呈劑量依賴性抑制TNF誘導的在人體主動脈內(nèi)皮上的細胞粘附作用當發(fā)生動脈硬化或其他大血管病變時大量的脂聯(lián)素會聚集在受損的血管壁上而導致患者脂聯(lián)素的消耗血漿脂聯(lián)素隨著動脈粥樣硬化的發(fā)展呈進行性下降低脂聯(lián)素血癥是冠狀動脈粥樣硬化發(fā)展的獨立危險因子脂聯(lián)素缺乏小鼠在動脈發(fā)生損傷的時候表現(xiàn)為嚴重的內(nèi)膜增厚使用外源性脂聯(lián)素可使內(nèi)膜增殖得到改善男性的脂聯(lián)素往往低于女性有人認為這可能是女性冠心病發(fā)病率低于男性的一個原因最近發(fā)生過心血管疾病患者脂聯(lián)素水平降低脂聯(lián)素每升高1μg/ml心血管的危險性則下降3%脂聯(lián)素可降低腫瘤壞死因子TNF-α刺激的粘附分子的表達抑制外周單核細胞的生長和炎癥因子的釋放具有保護內(nèi)皮抗炎拮抗動脈粥樣硬化的作用它的水平與甘油三酯載脂蛋白呈負相關與高密度脂蛋白及載脂蛋白A-I呈正相關。本課題通過細胞水平和動物水平兩個部分來探討脂聯(lián)素對膽固醇逆轉(zhuǎn)運的影響。選擇脂聯(lián)素基因敲除小鼠(Adiponectin-/-GeneKnockOutMice)作為研究動物,連續(xù)8周堅持高脂飼養(yǎng),建立動脈粥樣硬化模型。對脂聯(lián)素組動物血脂水平改變情況進行檢測;小鼠注射3H-TC后,經(jīng)液閃計數(shù)儀對脂聯(lián)素處理后動物肝臟、血清、糞便內(nèi)含有的膽固醇流出量進行檢測;經(jīng)Western-blot、PCR法對脂聯(lián)素處理后動物ABCA1的mRNA水平、蛋白量進行檢測,深入的分析脂聯(lián)素對RCT產(chǎn)生的影響和相關的作用機理,為臨床上有效的防止疾病的發(fā)生發(fā)展給予一個新方向、新思路。1、脂聯(lián)素通過肝X受體α信號通路上調(diào)RAW264.7巨噬細胞中ABCA1、ABCG1的表達及意義目的:離體研究脂聯(lián)素APN是否是通過肝X受體α信號通路影響RAW264.7源性泡沫細胞內(nèi)含有的ABCA1、ABCG1表達的mRNA水平、蛋白量、膽固醇流出量、膽固醇總水平。方法:培養(yǎng)RAW264.7巨噬細胞給予ox-LDL誘導為泡沫細胞。使用實時熒光定量PCR和westernblot檢測ABCA1、ABCG1mRNA和蛋白的表達;液體閃爍計數(shù)測定荷脂THP-1巨噬細胞和RAW264.7巨噬細胞內(nèi)膽固醇流出率;高效液相色譜法檢測細胞內(nèi)膽固醇含量。結(jié)果:脂聯(lián)素通過LXRα信號通路上調(diào)RAW264.7 巨噬細胞中ABCA1、ABCG1表達。結(jié)論:脂聯(lián)素通過LXRα途徑提高RAW264.7巨噬細胞中的ABCA1、ABCG1表達和膽固醇流出。為預防和治療動脈粥樣硬化提供了理論基礎。2、脂聯(lián)素對APN-/-動脈粥樣硬化小鼠ABCA1表達及動脈粥樣硬化的影響目的:研究脂聯(lián)素對脂聯(lián)素基因敲除小鼠(APN-/-小鼠)體內(nèi)巨噬細胞膽固醇逆轉(zhuǎn)運的影響及其在抗動脈粥樣硬化中可能的作用機制。1.觀察脂聯(lián)素對ApoE-/-小鼠頸動脈粥樣硬化斑塊的作用;2.探討脂聯(lián)素對斑塊內(nèi)硝基化應激的作用及其可能機制;3.觀察脂聯(lián)素對斑塊局部血流剪切力的影響,探討其抑制斑塊的其他可能機制。方法:1.模型建立:選擇4周齡脂聯(lián)素基因敲除小鼠(Adiponectin-/-geneknockoutmice)30只,高脂喂養(yǎng)8周,建立動脈粥樣硬化模型。2.分組:動物隨機分為五組:空白對照組,50μg/(kg·d)干預組,150μg/(kg·d)干預組,200μg/(kg·d)干預組,250μg/(kg·d)干預組。3.方法:脂聯(lián)素干預4周后,向APN-/-小鼠腹腔注射乙酰化LDL與3 H-TC標記的RAW264.7 巨噬細胞懸液,酶法測定小鼠血清血脂水平,液閃計數(shù)儀測定小鼠肝臟、血清及糞便中3H-TC占腹腔注射3H-TC總量的百分比,RT-PCR及Western-blot檢測肝臟中ABCA1的mRNA及蛋白表達水平。結(jié)果:1.與對照組相比,脂聯(lián)素干預組血清TG、TC、LDL水平明顯降低,HDL升高;且此改變隨脂聯(lián)素呈劑量依賴性改變。2.對照組主動脈粥樣硬化病變明顯,光鏡下可見血管壁有大量脂質(zhì)沉積,有粥樣斑塊形成,有散在泡沫細胞;脂聯(lián)素干預組APN-/-小鼠的主動脈粥樣硬化病變程減輕,且隨脂聯(lián)素呈劑量依賴性改變。3.脂聯(lián)素干預組血清3 H-TC含量明顯降低(P0.05),肝臟及糞便中3 H-TC含量明顯升高(P0.05)。4.RT-PCR檢測結(jié)果顯示:與對照組相比,脂聯(lián)素干預組肝臟組織ABCA1的mRNA轉(zhuǎn)錄水平明顯提高,且隨脂聯(lián)素呈劑量依賴性增加(P0.05)。5.Western-blot結(jié)果顯示:與對照組相比,使用脂聯(lián)素干預的實驗組肝臟組織ABCA1的蛋白表達水平明顯提高,且隨脂聯(lián)素呈劑量依賴性增加(P0.05)。結(jié)論:1.脂聯(lián)素能夠降低血清TC、TG及LDL水平,提高HDL水平;2.脂聯(lián)素可以減輕小鼠主動脈粥樣硬化;3.脂聯(lián)素可以增加血清膽固醇流出率;4.脂聯(lián)素能夠呈劑量依賴性上調(diào)肝臟組織中ABCA1的mRNA及蛋白表達。脂聯(lián)素通過上調(diào)ABCA1來促進膽固醇逆轉(zhuǎn)運,促進細胞內(nèi)膽固醇流出,從而延緩動脈粥樣硬化的發(fā)生及發(fā)展,為心血管疾病的防治提供了新思路。
[Abstract]:At present, in the world, the incidence and mortality of cardiovascular diseases are located in the first few places, and there is a major threat to people's physical and mental health. At present, about 230 million people with cardiovascular disease in China, about 3 million of them died of the disease. The Atherosclerosis (AS) is the key pathological basis in cardiovascular and cerebrovascular diseases. The lipid metabolism disorder characterized by abnormal cholesterol metabolism is an important pathogenic factor; the most important pathological feature of the disease is that macrophages can remove high levels of lipid producing foam cells. Based on the above background, researchers are keen to explore the mechanism of the development of atherosclerotic lesions and how to avoid foamy cells. Reverse Cholesterol ransport (RCT) refers to the transfer of free cholesterol in cells to the cell and to the liver and eventually expelled the body. The whole process of RCT includes the following steps: the initial peripheral cells contain a large number of cholesterin through the mediating of transporters such as ABCA1 and ABCG1, and then combined with apolipoprotein, HDL, which produces mature state, and then as the blood system aggregated to the liver, and finally excreted the.ATP binding cassette transporter (Binding Cassette Transporter, ABC) belonging to the most present membrane transport family. The ATP tri triphosphate binding cassette transporter A1 (ABCA1) is the most prominent transporter in transport, which helps the cell Cholesterol efflux. Under the action of ABCA1 transporter, lipid may occur Exodus, then combine with apoA-I, and then produce a certain level of phospholipid -apoA-I complex, and can esterification the extracellular free state of cholesterol, and eventually produce a mature HDL, with the blood system aggregation in the liver, and then able to be produced by the liver. Bile salts, and fecal excretion of [1-3]., increase the level of RCT to help prevent AS lesions. Related research results suggest that the number of High Density Lipoprotein Cholesterol, HDL-C is significantly negatively correlated with the possibility of atherosclerosis in the body, and.HDL-C antagonists the main pathogenesis of atherosclerosis The process is mediated by the mediating RCT process, in which RCT can transport a large amount of cholesterol contained in the peripheral tissue through HDL-C to the liver in the form of bile acid, which is currently recognized by researchers in the related fields as a key mechanism for anti atherosclerosis. In RCT, ABCA1 is beneficial to the transport of phosphorus in cells and to the transport of cholesterol to HDL-C precursors apoA-I. New HDL-C, and then start RCT, so ABCA1 plays an extremely important starting speed limit in the new generation of RCT and HDL-C. So can the anti transport of cholesterol be promoted to become a widely concerned target of anti atherosclerosis by regulating the expression of ABCA1 protein. Adiponectin (Adiponectin) is mainly derived from adipocytes and can play the pancreas. Isosin resistance, anti atherosclerotic and anti-inflammatory effects. Studies have shown that there is a lower level of adiponectin in the serum of patients with obesity, hypertension, diabetes, myocardial damage, atherosclerosis and other patients. And many clinical trials show that the concentration of adiponectin is significantly reduced with hypertension, vascular endothelial damage, coronary heart disease and myocardial infarction. The development of the disease is closely related to [4]. in the process of AS disease. Adiponectin can inhibit the differentiation and reproduction of vascular smooth muscle cells, avoid the continuous transformation of macrophages into foam cells, and make adiponectin play the anti AS effect in endothelial cells. The effect of lipoprotein on the reverse transfer of cholesterol in macrophages and its effect on the reverse transport of cholesterol in macrophages and the effect of adiponectin on the reverse transport of cholesterol in macrophages and the effect of adiponectin and its effect on the reverse transport of cholesterol in macrophages and the effect of adiponectin and its effect on the reverse transport of cholesterol in macrophages Mechanism in the early stage of coronary atherosclerotic AS the endothelial cells can be activated by inflammatory cells to be activated on the vascular wall and are dose-dependent inhibition of TNF induced adhesion on the human aortic endothelium. When atherosclerosis or other large vascular lesions occur, a large number of adiponectin will accumulate on the damaged vascular wall and cause the disease. Adiponectin consumes plasma adiponectin with the development of atherosclerosis progressive decline of adiponectin is an independent risk factor for the development of coronary atherosclerosis. Adiponectin is an independent risk factor for the development of coronary atherosclerosis. Sexual adiponectin is often lower than that of women who think that it may be a reason that the incidence of coronary heart disease in women is lower than that of men. The growth of peripheral mononuclear cells and the release of inflammatory factors can protect the endothelium from anti-inflammatory and antagonistic atherosclerosis. Its level is negatively correlated with the triglyceride apolipoprotein and is positively related to high density lipoprotein and apolipoprotein A-I. This topic is to explore the adiponectin to cholesterol through two parts of cell level and animal level. An adiponectin gene knockout mouse (Adiponectin-/-GeneKnockOutMice) was selected as a study animal to keep high fat feeding for 8 weeks and establish atherosclerosis model. The changes of blood lipid levels in adiponectin groups were detected. After 3H-TC injection, the liver and blood of adiponectin treated animal liver and blood were treated with liquid flicker. The amount of cholesterol efflux contained in the feces was detected, and the mRNA level and the protein amount of ABCA1 after adiponectin treatment were detected by Western-blot and PCR. The effect of adiponectin on the production of RCT and the related mechanism were deeply analyzed, so as to provide a new direction for the clinical effective prevention and development of the disease, a new idea of.1, fat. The expression and significance of ABCA1 and ABCG1 in RAW264.7 macrophages was up-regulated through the hepatic X receptor alpha signaling pathway: in vitro whether adiponectin APN affects the ABCA1 in RAW264.7 derived foam cells through the X receptor alpha signaling pathway of the liver, the mRNA level of ABCG1 expression, the amount of protein, the amount of cholesterol efflux, the total cholesterol level. Ox-LDL induced RAW264.7 macrophages were induced as foam cells. The expression of ABCA1, ABCG1mRNA and protein was detected by real-time fluorescence quantitative PCR and Westernblot; the liquid scintillation counting was used to determine the cholesterol efflux rate in lipid THP-1 macrophages and RAW264.7 macrophages. High performance liquid chromatography was used to detect the intracellular cholesterol content. Results: adiponectin. The expression of ABCA1 and ABCG1 in RAW264.7 macrophages was up-regulated through the LXR alpha signaling pathway. Conclusion: Adiponectin enhances the ABCA1, ABCG1 expression and cholesterol efflux in RAW264.7 macrophages through LXR alpha pathway. It provides a theoretical basis for the prevention and treatment of atherosclerosis,.2, ABCA1 expression and atherosclerosis in APN- / - atherosclerotic mice Objective: To study the effect of adiponectin on the reverse transport of cholesterol in macrophages in adiponectin gene knockout mice (APN-/- mice) and the possible mechanism of action in anti atherosclerosis.1. to observe the effect of adiponectin on carotid atherosclerotic plaques in ApoE-/- mice; 2. to explore the effect of adiponectin on the nitrocellulose stress in the plaque. The effect and possible mechanism of the 3. adiponectin on plaque local blood flow shear force and other possible mechanisms to inhibit the plaque. Methods: 1. model establishment: 4 weeks old adiponectin gene knockout mice (Adiponectin-/-geneknockoutmice) 30, high fat feeding for 8 weeks, the establishment of atherosclerotic model.2. grouping: Animal random They were divided into five groups: blank control group, 50 g/ (kg d) intervention group, 150 mu g/ (kg / D) intervention group, 200 g/ (kg. D) intervention group and 250 mu g/ (kg d) intervention group. After 4 weeks of adiponectin intervention, acetylation and 3 macrophage suspension were injected into the abdominal cavity of mice. The serum lipid level of mice was measured by enzyme method, and the liquid flash counting instrument was determined. The percentage of 3H-TC in the liver, serum and feces of mice accounted for the total amount of 3H-TC intraperitoneally injected. RT-PCR and Western-blot were used to detect the mRNA and protein expression levels of ABCA1 in the liver. Results: 1. compared with the control group, the serum TG, TC, LDL level and HDL increased in the adiponectin intervention group, and the changes were dose-dependent with the adiponectin to change the.2. control group. The atherosclerotic lesions were obvious. There was a large amount of lipid deposition in the vascular wall, the formation of atheromatous plaque and the foam cells. The atherosclerotic lesion of the APN-/- mice in the adiponectin intervention group alleviated, and the serum 3 H-TC content of.3. adiponectin was significantly decreased with the dose dependent change of adiponectin (P0.05), the liver and the liver were significantly decreased. 3 H-TC content in the feces was significantly increased (P0.05).4.RT-PCR test results showed that the mRNA transcriptional level of ABCA1 in the liver tissue of the adiponectin intervention group was significantly higher than that of the control group, and the dose dependent increase with adiponectin (P0.05).5.Western-blot results showed that the liver tissue ABCA1 using adiponectin intervention compared with the control group. The level of protein expression increased obviously and increased with adiponectin in a dose-dependent manner (P0.05). Conclusion: 1. adiponectin can reduce the level of serum TC, TG and LDL, increase the level of HDL; 2. adiponectin can reduce the atherosclerosis of aorta in mice; 3. adiponectin can increase the rate of serum cholesterol efflux; 4. adiponectin can increase the liver in a dose dependent manner. The expression of mRNA and protein in the tissue of ABCA1. Adiponectin promotes the reverse transport of cholesterol by up regulation of ABCA1 and promotes intracellular cholesterol efflux, thus delaying the occurrence and development of atherosclerosis and providing a new idea for the prevention and treatment of cardiovascular diseases.

【學位授予單位】：山西醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R54

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