本文選題：動(dòng)脈粥樣硬化　切入點(diǎn)：U937源性泡沫細(xì)胞　出處：《復(fù)旦大學(xué)》2008年碩士論文　論文類(lèi)型：學(xué)位論文

【摘要】： 背景: 動(dòng)脈粥樣硬化疾病已成為威脅國(guó)人健康的主要疾病之一,而動(dòng)脈粥樣硬化(atherosclerosis,AS)的發(fā)生與局部血栓形成密切相關(guān)。組織因子(tissue factor,TF)是血栓形成的起始因子,組織因子途徑抑制物(tissue factor pathway inhibitor,TFPI)作為T(mén)F的生理抑制劑,它有兩種同族異形體,TFPI-1和TFPI-2。大量研究證實(shí)TFPI-1在抑制血栓形成和血管重塑等方面發(fā)揮重要作用;TFPI-2與粥樣斑塊的穩(wěn)定性相關(guān),而在動(dòng)脈粥樣斑塊形成階段的作用尚無(wú)相關(guān)研究,我們前期動(dòng)物模型研究初步提示TFPI-2在其中具有一定作用。單核細(xì)胞源性的泡沫細(xì)胞是粥樣斑塊早期形成階段的典型病變,貫穿AS疾病發(fā)生發(fā)展。我們希望以建立泡沫細(xì)胞模型為研究的切入點(diǎn),初步探討TFPI-2與AS斑塊形成之間的聯(lián)系。 目的: 1.研究TFPI-2蛋白在U937單核細(xì)胞和U937源性泡沫細(xì)胞的表達(dá)定位; 2.觀(guān)察氧化型低密度脂蛋白(oxidized low density lipoprotein,ox-LDL)誘導(dǎo)U937源性泡沫細(xì)胞形成過(guò)程中,TFPI-2蛋白表達(dá)和基因水平的變化規(guī)律; 3.觀(guān)察外源性hrTFPI-2蛋白干預(yù),對(duì)U937源性泡沫細(xì)胞胞內(nèi)膽固醇蓄積的影響,以確定TFPI-2與泡沫細(xì)胞形成是否存在聯(lián)系,并探討可能的機(jī)制和意義; 4.觀(guān)察泡沫細(xì)胞形成中,影響TFPI-2表達(dá)的因素。與人臍靜脈內(nèi)皮細(xì)胞(human umbilical vein endothelial cell,HUVEC)共同培養(yǎng),U937源性泡沫細(xì)胞中TFPI-2蛋白表達(dá)和基因水平的變化規(guī)律,并探討該變化可能存在機(jī)制及意義。 方法: 1.采用改良沉淀法提取人血漿低密度脂蛋白(low density lipoprotein,LDL),硫酸銅氧化制備ox-LDL,與U937單核細(xì)胞共同孵育,建立泡沫細(xì)胞模型。胞內(nèi)膽固醇定量測(cè)定和油紅O染色定性評(píng)價(jià)建模成功。 2.采用雙重細(xì)胞免疫熒光檢測(cè)TFPI-2蛋白在泡沫細(xì)胞中的表達(dá)定位。 3.在ox-LDL誘導(dǎo)U937源性泡沫細(xì)胞形成過(guò)程中,分設(shè)觀(guān)察時(shí)間點(diǎn)收集細(xì)胞,采用逆轉(zhuǎn)錄聚合酶鏈反應(yīng)(reverse transcriptase-polymerase chain reaction,RT-PCR)半定量分析和熒光定量聚合酶鏈反應(yīng)(real-time fluorescent quantitativePCR,FQ-PCR)相對(duì)定量分析TFPI-2基因的動(dòng)態(tài)變化;采用時(shí)間免疫分辨熒光(time resolved fluorometric immunoassay,TRFIA)定量檢測(cè)TFPI-2蛋白表達(dá)水平。 4.設(shè)rhTFPI-2不同濃度組(1nM,10nM,50nM,100nM,200nM),分別加入含ox-LDL終濃度為80μg/ml,細(xì)胞密度為15×10~4個(gè)/ml的U937細(xì)胞培液中,共同孵育48h后提取細(xì)胞脂質(zhì),以脂質(zhì)測(cè)定試劑盒檢測(cè),計(jì)算胞內(nèi)膽固醇含量。 5.將HUVEC和U937細(xì)胞共同培養(yǎng),分別用RT-PCR和TRFIA檢測(cè)TFPI-2基因和蛋白的表達(dá)水平。 6.用SPSS 10.0軟件進(jìn)行統(tǒng)計(jì)分析,計(jì)量資料以均數(shù)±標(biāo)準(zhǔn)差((?)±s)表示,組間比較采用成組t檢驗(yàn)分析:P＜0.05表明統(tǒng)計(jì)學(xué)有顯著性差異。 結(jié)果: 1.泡沫細(xì)胞模型的建立和鑒定: 1.1 ox-LDL的制備和鑒定: 分離冠心病患者血漿LDL,經(jīng)5%瓊脂糖電泳證實(shí)為單一條帶。由硫代巴比妥酸反應(yīng)物質(zhì)(thiobarbituric acid reactive substance,TBARS)值反映LDL氧化程度。新鮮LDL值為3.81±0.53 nM MDA/mg,而ox-LDL的值為31.95±2.93 nMMDA/mg,ox-LDL的TBARS值大于LDL的5倍以上,兩者相比有顯著統(tǒng)計(jì)學(xué)差異(P＜0.05),提示ox-LDL脂質(zhì)被有效氧化。同時(shí)ox-LDL瓊脂糖電泳相對(duì)遷移率(relmive electrophoresis mobility,REM)升高,亦證實(shí)ox-LDL制備成功。 1.2 ox-LDL造模濃度確立和泡沫細(xì)胞模型鑒定: 以細(xì)胞內(nèi)膽固醇定量和油紅染色定性,作為評(píng)價(jià)泡沫細(xì)胞的指標(biāo)。不同濃度組的ox-LDL與U937細(xì)胞共同孵育48h后,80mg/L ox-LDL組的胞內(nèi)膽固醇酯/總膽固醇(CE/TC)值大于50%,光鏡下觀(guān)察油紅O染色,胞漿內(nèi)出現(xiàn)大量紅染顆粒和脂質(zhì)空泡;80mg/L LDL組和60mg/L ox-LDL組的CE/TC值均低于50%;120mg/L ox-LDL組的CE/TC值雖大于50%,但凋亡細(xì)胞數(shù)量顯著增多,不利于后續(xù)實(shí)驗(yàn);故選擇80mg/Lox-LDL與U937細(xì)胞(細(xì)胞密度15×10~4個(gè)/ml)共孵育48h,確定為最佳建模條件。 2.TFPI-2蛋白在泡沫細(xì)胞內(nèi)的表達(dá)定位: 雙重細(xì)胞免疫熒光證實(shí),TFPI-2蛋白主要定位于U937源性泡沫細(xì)胞胞漿,與TF蛋白有類(lèi)似分布;與正常U937細(xì)胞相比較,泡沫細(xì)胞中TFPI-2蛋白和TF蛋白的分布情況更趨一致。HUVEC中也存在類(lèi)似情況,且在氧化損傷情況下,細(xì)胞在形態(tài)學(xué)上的改變,熒光信號(hào)強(qiáng)度較正常情況下稍有減弱。 3.泡沫細(xì)胞形成過(guò)程中TFPI-2蛋白及基因表達(dá)的動(dòng)態(tài)變化: TRFIA檢測(cè)發(fā)現(xiàn),U937與ox-LDL孵育6h后,TFPI-2蛋白表達(dá)量明顯增高達(dá)峰值;而在共同孵育6h至48h期間,TFPI-2蛋白表達(dá)量降低;孵育12h后,TFPI-2蛋白表達(dá)量基本低于正常水平。以看家基因β-action為內(nèi)參,FQ-PCR結(jié)果顯示,U937與ox-LDL孵育6h,TFPI-2 mRNA表達(dá)上調(diào)達(dá)至峰值;而6h至48h期間TFPI-2 mRNA表達(dá)下調(diào)。FQ-PCR結(jié)果與蛋白水平的變化相一致。 4.外源性TFPI-2蛋白對(duì)泡沫細(xì)胞胞內(nèi)膽固醇的影響: 分設(shè)rhTFPI-2不同濃度組(1nM,10nM,50nM,100nM,200nM),加入含ox-LDL終濃度為80μg/ml的U937細(xì)胞培液中。比較各濃度組與空白組(OnM)之間數(shù)據(jù)發(fā)現(xiàn):1nM組干預(yù)48h后TC和CE/TC水平無(wú)明顯統(tǒng)計(jì)學(xué)差異(FC:24.733±1.504 vs 23.130±2.341,P＞0.1:TC::50.775±2.831 vs 52.226±1.662,P＞0.1),CE/TC為51.29%;在10nM,50nM,100nM,200nM組干預(yù)48h后,各組FC值分別為21.041±1.702、20.911±2.012、20.790±1.127、20.552±2.733;各組TC值分別為38.707±2.011、34.956±2.562、32.118±1.920、32.168±3.023;各組CE/TC值分別為45.64%、40.18%、35.27%、36.11%,各組TC和CE/TC均明顯降低,與空白組(0nM)相比有顯著統(tǒng)計(jì)學(xué)差異(P＜0.05)。外源性TFPI-2蛋白干預(yù)可減少泡沫細(xì)胞的胞內(nèi)膽固醇蓄積,該作用呈一定濃度依賴(lài)方式,TFPI-2與泡沫細(xì)胞形成存在關(guān)聯(lián)。 5.內(nèi)皮細(xì)胞對(duì)泡沫細(xì)胞形成中TFPI-2表達(dá)的影響: 5.1 ox-LDL對(duì)內(nèi)皮細(xì)胞TFPI-2表達(dá)的影響: HUVEC與ox-LDL(80mg/L)共同孵育48h,其TFPI-2蛋白表達(dá)量呈先升高后降低的動(dòng)態(tài)改變;共同孵育24h后,其TFPI-2蛋白表達(dá)量達(dá)峰值。RT-PCR結(jié)果顯示,在ox-LDL作用24h至48h期間,TFPI-2 mRNA的水平持續(xù)增高。提示氧化損傷可能導(dǎo)致內(nèi)皮細(xì)胞TFPI-2蛋白表達(dá)障礙。 5.2內(nèi)皮細(xì)胞對(duì)泡沫細(xì)胞形成過(guò)程中TFPI-2蛋白表達(dá)的影響: 與單獨(dú)培養(yǎng)組比較,U937細(xì)胞與HUVEC共同培養(yǎng)時(shí)TFPI-2的蛋白表達(dá)量明顯上調(diào);隨著ox-LDL氧化損傷時(shí)間的延長(zhǎng),盡管共培養(yǎng)組U937細(xì)胞的TFPI-2蛋白表達(dá)呈下調(diào)趨勢(shì),但仍高于U937單獨(dú)培養(yǎng)組(0h:8.106±0.971 vs 6.291±1.272,P＜0.05;24h:6.219±1.704 vs 4.065±0.551,P＜0.05;48h:5.982±1.392vs 4.163±1.110,P＜0.05)。RT-PCR結(jié)果顯示,U937細(xì)胞和HUVEC共同培養(yǎng)48h后,U937細(xì)胞TFPI-2 mRNA水平較單獨(dú)培養(yǎng)組明顯上調(diào)。 結(jié)論: 1.80 mg/L ox-LDL加入細(xì)胞密度為15×10~4個(gè)/ml的U937細(xì)胞培液中孵育48h,可成功建立U937源性泡沫細(xì)胞模型。 2.TFPI-2蛋白主要定位于U937源性泡沫細(xì)胞胞漿中,與TF蛋白有相似分布。正常U937細(xì)胞中有同樣的分布規(guī)律,但在泡沫細(xì)胞中TFPI-2蛋白和TF蛋白的分布更趨一致。 3.U937源性泡沫細(xì)胞形成過(guò)程中,早期TFPI-2蛋白和基因水平迅速上調(diào),而后期TFPI-2蛋白和基因水平明顯下調(diào),低于正常值水平。在泡沫細(xì)胞形成過(guò)程中存在TPFI-2蛋白和基因水平的相對(duì)缺乏。 4.外源性中高濃度的rhTFPI-2蛋白可改善U937源性泡沫細(xì)胞形成過(guò)程中胞內(nèi)膽固醇蓄積,該效應(yīng)呈一定的濃度依賴(lài)方式;低濃度的rhTFPI-2蛋白無(wú)此效應(yīng),提示TFPI-2與泡沫細(xì)胞形成存在聯(lián)系。 5.與HUVEC共同培養(yǎng),可以改善U937源性泡沫細(xì)胞形成過(guò)程中存在的TFPI-2蛋白和基因相對(duì)缺乏。
[Abstract]:Background:
Atherosclerotic disease has become one of the main diseases that threaten the health of the Chinese people, and atherosclerosis (atherosclerosis, AS) and the occurrence of thrombosis are closely related to tissue factor (tissue factor, TF) is the initial factor of thrombosis, tissue factor pathway inhibitor complexes (tissue factor pathway inhibitor, TFPI) as a physiological inhibitor of TF. It has two isoforms TFPI-1 and TFPI-2. family, a large number of studies have confirmed that TFPI-1 play an important role in inhibiting thrombosis and vascular remodeling; stability of TFPI-2 and atherosclerotic plaque, and in the formation of atherosclerosis plaque stage has not been studied in our previous animal model study indicates that TFPI-2 has a certain role in the single. Monocyte derived foam cells of atherosclerotic plaque formation is the typical early stage of disease, through the development of AS disease. We hope to build The vertical foam cell model is the breakthrough point of the study, and the relationship between TFPI-2 and AS plaque formation is preliminarily discussed.
Objective:
1. the expression of TFPI-2 protein in U937 mononuclear cells and U937 derived foam cells was studied.
2., we observed the change of TFPI-2 protein expression and gene level during the formation of U937 derived foam cells induced by oxidized low density lipoprotein (oxidized low density lipoprotein (ox-LDL)).
3., we observed the effect of exogenous hrTFPI-2 protein intervention on the intracellular cholesterol accumulation of U937 derived foam cells to determine whether there is a relationship between TFPI-2 and foam cell formation, and to explore the possible mechanism and significance.
4. to observe the formation of foam cells, the influence factors of TFPI-2 expression. With human umbilical vein endothelial cells (human umbilical vein endothelial cell, HUVEC) co culture, the expression of TFPI-2 protein and gene level of U937 derived foam cells, and to explore the possible mechanism of change and significance.
Method:
1., we use improved precipitation method to extract low density lipoprotein (LDL) from human plasma, prepare ox-LDL by copper sulfate oxidation, and incubate with U937 mononuclear cells, and establish foam cell model. Intracellular cholesterol quantitative determination and oil red O staining qualitative evaluation and modeling are successful.
2. the expression of TFPI-2 protein in foamy cells was detected by double cell immunofluorescence (double cell immunofluorescence).
The formation process of 3. in ox-LDL induced U937 derived foam cells, divided into the observation time points were collected by reverse transcriptase polymerase chain reaction (reverse transcriptase-polymerase chain reaction, RT-PCR) semi quantitative analysis and fluorescence quantitative polymerase chain reaction (real-time fluorescent quantitativePCR, FQ-PCR) the relative quantitative analysis of dynamic change of TFPI-2 gene by using time resolved fluorescence (immune; time resolved fluorometric immunoassay TRFIA), the expression level of quantitative detection of TFPI-2 protein.
4., set up different concentrations of rhTFPI-2 (1nM, 10nM, 50nM, 100nM, 200nM), add ox-LDL containing 80 ox-LDL g/ml, and 15 cell 10~4 /ml /ml cells, respectively, and extract the cell lipids after incubation.
5. HUVEC and U937 cells were co cultured, and the expression level of TFPI-2 gene and protein was detected by RT-PCR and TRFIA respectively.
6., statistical analysis was done with SPSS 10 software. The measurement data were expressed by mean + standard deviation ((+) s). The comparison between groups was analyzed by group t test: P < 0.05 showed statistically significant difference.
Result:
1. the establishment and identification of the foam cell model:
1.1 ox-LDL preparation and identification:
Separation of plasma LDL in patients with coronary heart disease, by 5% agarose gel electrophoresis confirmed as single bands. By thiobarbituric acid reactive substances (thiobarbituric acid, reactive substance, TBARS LDL) value to reflect the degree of oxidation. The fresh LDL was 3.81 + 0.53 nM MDA/mg, and the value of ox-LDL is 31.95 + 2.93 nMMDA/mg, ox-LDL value of TBARS more than 5 times LDL, there was a statistically significant difference between the two compared (P < 0.05), suggesting that ox-LDL is effective and lipid oxidation. Ox-LDL agarose gel electrophoresis. The relative migration rate (relmive electrophoresis mobility, REM) increased, also confirmed the successful preparation of ox-LDL.
1.2 ox-LDL model concentration establishment and foam cell model identification:
The cellular cholesterol quantitative and qualitative evaluation of oil red staining, as foam cell index. Different concentrations of ox-LDL and U937 cells were incubated for 48h, total cholesterol / 80mg/L cholesterol ester group ox-LDL intracellular (CE/TC) value is greater than 50%, under the light microscope oil red O staining, the cytoplasm appeared large red dye particles and lipid vacuoles; 80mg/L LDL group and 60mg/L ox-LDL group CE/TC values were less than 50% 120mg/L; group ox-LDL CE/TC value is greater than 50%, but the number of apoptotic cells increased significantly, is not conducive to the subsequent experiment; the 80mg/Lox-LDL and U937 cells (cell density of 15 * 10~4 /ml) Co incubated with 48h. To determine the best condition of modeling.
Expression of 2.TFPI-2 protein in foamy cells:
Double immunofluorescence confirmed that TFPI-2 protein was mainly localized in U937 derived foam cells have a similar distribution with TF protein; compared with normal U937 cells, the situation is similar to the distribution of more consistent.HUVEC TFPI-2 protein and TF protein in the foam cells, and oxidative damage in the case of cells in morphology the change of fluorescence signal intensity is normally weakened slightly.
3. the dynamic changes of TFPI-2 protein and gene expression during the formation of foamy cells:
TRFIA detection, U937 and ox-LDL after 6h incubation, the expression of TFPI-2 protein was obviously increased up to the peak; and during the incubation of 6h to 48h, the expression of TFPI-2 protein decreased; after 12h incubation, TFPI-2 protein expression was lower than the normal level. The basic housekeeping gene beta -action as a reference, the results of FQ-PCR showed that U937 and ox-LDL were incubated with 6h, TFPI-2 expression of mRNA was up-regulated to peak; consistent during 6h to 48h TFPI-2 mRNA expression and down-regulation of.FQ-PCR protein level results.
4. the effect of exogenous TFPI-2 protein on intracellular cholesterol in foam cells:
RhTFPI-2 is divided into different concentration groups (1nM, 10nM, 50nM, 100nM, 200nM, ox-LDL) with a final concentration of U937 cell culture medium 80 g/ml. Compared with each concentration group and blank control group (OnM) data found no statistically significant between group 1nM and CE/TC TC after the intervention of 48h (24.733 + FC: level difference 1.504 vs 23.130 + 2.341, P > 0.1:TC:: 50.775 + 2.831 vs 52.226 + 1.662, P > 0.1), CE/TC 51.29%; in 10nM, 50nM, 100nM, 200nM group 48h after the intervention, the FC values of each group were 21.041 + 1.702,20.911 + 2.012,20.790 + 1.127,20.552 + 2.733; group TC = 38.707 + 2.011,34.956. 2.562,32.118 + 1.920,32.168 + 3.023; the CE/TC values of each group were 45.64%, 40.18%, 35.27%, 36.11%, TC and CE/TC groups were significantly decreased, and the blank group (0nM) compared with significant difference (P < 0.05). The intervention of exogenous TFPI-2 protein can reduce the intracellular cholesterol less foam cell accumulation, and the effect was In a certain concentration dependent manner, TFPI-2 is associated with the formation of foam cells.
5. the effect of endothelial cells on the expression of TFPI-2 in the formation of foam cells:
The effect of 5.1 ox-LDL on the expression of TFPI-2 in endothelial cells:
HUVEC and ox-LDL (80mg/L) were incubated with 48h, the expression of TFPI-2 protein showed the dynamic change increased first and then decreased; after 24h incubation, the expression of TFPI-2 protein reached the peak.RT-PCR results show that during the ox-LDL 24h to 48h, TFPI-2 continued to increase the level of mRNA. Suggested that oxidative damage may lead to endothelial expression the expression of TFPI-2.
5.2 the effect of endothelial cells on the expression of TFPI-2 protein during the formation of foam cells:
With the single culture group, U937 and HUVEC cells co cultured with the TFPI-2 protein expression was significantly up-regulated; with the prolonged oxidative ox-LDL damage, although the co culture group U937 cells TFPI-2 protein expression decreased, but still higher than that of U937 cultured alone. (0h:8.106 + 0.971 vs 6.291 + 1.272, P < 0.05; 24h:6.219 4.065 + 1.704 vs + 0.551, P < 0.05; 48h:5.982 + 1.392vs 4.163 + 1.110, P < 0.05) the results of.RT-PCR showed that U937 and HUVEC cells after cultured 48h U937 cells, TFPI-2 mRNA levels were significantly increased compared with single culture.
Conclusion:
1.80 mg/L ox-LDL incubated 48h in the U937 cell culture of 15 x 10~4 /ml cells, and the U937 derived foam cell model could be successfully established.
2.TFPI-2 protein is mainly located in cytoplasm of U937 derived foam cells, and has similar distribution with TF protein. Normal U937 cells have the same distribution pattern, but the distribution of TFPI-2 protein and TF protein is more consistent in foam cells.
In the process of 3.U937 derived foam cell formation, the TFPI-2 protein and gene level increased rapidly at the early stage, while the TFPI-2 protein and gene level in the later stage were significantly down regulated, which was lower than the normal level. There was a relative lack of TPFI-2 protein and gene level in the foam cell formation process.
4., exogenous high and high concentration of rhTFPI-2 protein can improve intracellular cholesterol accumulation during the formation of U937 derived foam cells. The effect is in a concentration dependent manner. Low concentration of rhTFPI-2 protein has no such effect, suggesting that TFPI-2 is related to foam cell formation.
The co culture of 5. with HUVEC can improve the relative lack of TFPI-2 protein and gene in the formation of U937 derived foam cells.

【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2008
【分類(lèi)號(hào)】：R363

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