本文選題：冠心病 + 高密度脂蛋白�。� 參考：《北京協(xié)和醫(yī)學(xué)院》2016年博士論文

【摘要】：第一部分血漿HDL組分apoCⅢ與冠心病的關(guān)系及他汀治療對其影響研究背景高密度脂蛋白(high density lipoprotein, HDL)作為膽固醇逆向轉(zhuǎn)運(yùn)(reverse cholesterol transfer, RCT)的載體,被認(rèn)為是心血管系統(tǒng)重要的保護(hù)因子。眾多的流行病學(xué)和臨床研究已經(jīng)發(fā)現(xiàn)并證實了冠心病(coronary heart disease, CHD)和血漿中HDL膽固醇(HDL cholesterol, HDL-c)水平具有負(fù)相關(guān)、而和血漿中低密度脂蛋白膽固醇(low density lipoprotein cholesterol, LDL-c)具有正相關(guān)的關(guān)系。作為一類有效的調(diào)脂藥物,他汀類(statin)藥物則能通過降低血漿中致粥樣硬化脂質(zhì)的水平和其抗炎作用發(fā)揮保護(hù)心血管的作用。隨著研究的不斷深入,人們發(fā)現(xiàn)并非所有的CHD患者都存在低HDL-c水平或高LDL-c水平的情況。近年來逐漸有研究發(fā)現(xiàn),HDL的生物學(xué)功能和其自身組分的變化以及機(jī)體的病理生理狀態(tài)密切相關(guān),CHD的發(fā)生發(fā)展也與HDL中一些組分的變化相關(guān),而非單純地和血漿中HDL-c的水平相關(guān)。最近的研究發(fā)現(xiàn),CHD患者血漿HDL中存在較高的載脂蛋白CⅢ (apolipoprotein CⅢ, apoCⅢ)水平,其能夠更好地預(yù)測CHD的發(fā)生和進(jìn)展。但由于他汀藥物的普遍應(yīng)用,血漿HDL組分apoCⅢ的含量與CHD的關(guān)系以及他汀類藥物治療后對它們的影響目前仍不十分清楚。研究目的1.明確血漿HDL組分apoCⅢ的含量和CHD的關(guān)系。2.分析研究CHD患者他汀藥物治療后血漿HDL組分apoCⅢ的含量及其與其它血脂關(guān)系的變化。研究方法入選經(jīng)冠脈造影確診的CHD患者120例和非冠心病(non coronary heart disease, non-CHD)患者80例。所有CHD患者均接受他汀藥物治療,并在他汀治療3個月后接受隨訪。收集入選患者以及隨訪患者的臨床資料并采集空腹靜脈血,采用超速離心的方法提取血漿中HDL樣品,應(yīng)用ELISA的方法檢測血漿和HDL樣品中apoCⅢ的含量。統(tǒng)計學(xué)分析血漿HDL組分apoCⅢ的含量與CHD的關(guān)系以及他汀治療后對CHD患者血漿HDL組分apoCⅢ及其與CHD和血脂關(guān)系的影響。研究結(jié)果1.CHD患者血漿HDL組分apoCⅢ的含量顯著高于non-CHD患者(25.05±12.98μg/mgHDL vs 21.00±11.33 μg/mgHDL,p0.05),具有統(tǒng)計學(xué)意義。多因素風(fēng)險回歸分析顯示,在校正了其它危險因素的混雜影響后,血漿HDL組分apoCIII的含量依然是CHD獨(dú)立的風(fēng)險預(yù)測因子p0.05)。2.他汀藥物治療能夠顯著地降低CHD患者血漿中TC、LDL-c和apoB等致粥樣硬化血脂的水平p0.001),并升高血漿中HDL-c和apoAI等抗粥樣硬化血脂的水平p0.001),但同時也升高了CHD患者血漿HDL組分apoCⅢ的含量(24.26±14.80 μg/mgHDL vs 29.35±16.46μg/mgHDL,p0.05),差異具有統(tǒng)計學(xué)意義。3. non-CHD患者血漿HDL組分apoCⅢ和血漿中TG的水平具有顯著的正相關(guān)關(guān)系(R=0.62,p0.05),這種相關(guān)性在CHD患者血漿中減弱(R=0.24,p0.05),并在接受他汀治療后的CHD患者血漿中消失(R=0.11,p0.05)。而血漿HDL組分apoCⅢ和血漿中apoCⅢ水平之間的相關(guān)性并不受疾病狀態(tài)和他汀藥物的影響,無論是在non-CHD患者(R=0.35,p0.05)還是CHD患者(R=0.31,p0.05)以及他汀藥物治療后的CHD患者(R=0.35,p0.05)血漿中均有相關(guān)性。4.本研究中,我們并未發(fā)現(xiàn)血漿HDL組分apoCⅢ與血漿中HDL-c或LDL-c的水平具有明顯的相關(guān)性。小結(jié)1.CHD患者血漿HDL組分apoCⅢ的含量顯著高于non-CHD患者,血漿HDL組分apoCⅢ的含量和CHD之間具有正相關(guān)的關(guān)系。2.他汀治療能降低CHD患者血漿中致粥樣硬化血脂指標(biāo)和升高HDL-c的水平,但同時也升高了CHD患者血漿中HDL組分apoCⅢ的含量。第二部分ApoCⅢ在冠心病患者HDL促人臍靜脈內(nèi)皮細(xì)胞炎癥反應(yīng)中的作用及他汀治療對其影響研究背景高密度脂蛋白(high density lipoprotein, HDL)不僅是膽固醇逆向轉(zhuǎn)運(yùn)(reverse cholesterol transfer, RCT)的重要載體,其也能通過抗炎抗氧化等多種生物學(xué)效應(yīng)發(fā)揮對心血管系統(tǒng)的保護(hù)作用。眾多研究發(fā)現(xiàn),體內(nèi)的HDL水平與AS(atherosclerosis, AS)和冠心病(coronary heart disease, CHD)的發(fā)生和發(fā)展具有負(fù)相關(guān)的關(guān)系,升高血漿中HDL的水平能夠降低CHD的發(fā)病風(fēng)險。然而隨著研究的深入,人們發(fā)現(xiàn),進(jìn)一步升高CHD患者血漿中HDL的水平并不能得到更多的心血管獲益,HDL的生物學(xué)作用也和其組分改變以及機(jī)體的病理生理狀態(tài)密切相關(guān)。急性期反應(yīng)階段和終末期腎病患者血漿中的HDL對內(nèi)皮細(xì)胞(endothelial cell, EC)不再具有保護(hù)作用,反而具有一定的促進(jìn)炎癥反應(yīng)的作用,而CHD患者血漿HDL中升高的apoCⅢ在其血漿HDL促進(jìn)EC的凋亡中發(fā)揮著作用。鑒于apoCⅢ是一種具有促炎作用的載脂蛋白,目前仍不清楚CHD患者血漿HDL中升高的apoCⅢ在其血漿HDL促炎反應(yīng)中是否也發(fā)揮著類似的作用。他汀類(statin)藥物處了能夠降低血漿中致粥樣硬化脂質(zhì)的水平外,其還有一定的抗炎作用,從而發(fā)揮保護(hù)心血管的作用。鑒于CHD患者血漿HDL組分及其生物學(xué)功能的改變,但目前并不清楚他汀藥物治療是否能夠改善CHD患者血漿HDL的生物學(xué)功能。研究目的1.研究apoCⅢ促炎反應(yīng)的時間和劑量依賴性。2.研究apoCⅢ在CHD患者HDL促炎反應(yīng)中的作用。3.研究他汀藥物治療后對冠心病患者血漿HDL促炎反應(yīng)的影響以及apoCⅢ在他汀治療后CHD患者血漿HDL促炎反應(yīng)中的作用。研究方法以體外培養(yǎng)的人臍靜脈內(nèi)皮細(xì)胞(human umbilical venous endothelial cell, HUVEC)為研究對象,模擬人體環(huán)境利用同一劑量的apoCⅢ刺激HUVEC不同的時間和利用不同劑量的apoCⅢ刺激HUVEC研究apoCⅢ促炎反應(yīng)的時間和劑量依賴性。并利用提取的CHD患者血漿HDL樣品在100μg/ml的條件下刺激HUVEC評價其促炎反應(yīng)的作用,然后利用apoCⅢ抗體中和CHD患者血漿HDL組分apoCIII的作用后促炎反應(yīng)的變化探索apoCIII在CHD患者血漿HDL促炎反應(yīng)中的作用。通過比較他汀藥物治療前后CHD患者血漿HDL促炎反應(yīng)的變化評價他汀治療對CHD患者血漿HDL促炎反應(yīng)的影響,并利用抗體中和的方法探索apoCIII在他汀治療后CHD患者血漿HDL促炎反應(yīng)中的作用。本部分研究中,我們以血管細(xì)胞黏附分子(vascular cell adhesion molecule 1, VCAM-1),細(xì)胞間黏附分子(intercellular adhesion molecule 1, ICAM-1),單核細(xì)胞趨化蛋白1 (monocyte chemotactic protein 1, MCP-1)和白介素6(interleukin 6, IL-6)等炎性因子的分泌和表達(dá)來評價促炎反應(yīng)情況。研究結(jié)果1.研究發(fā)現(xiàn),隨著apoCⅢ作用于HUVEC濃度的增加或時間的延長,炎性因子IL-6和MCP-1的分泌以及VCAM-1和ICAM-1的表達(dá)逐漸增多和增加。2. apoCⅢ在CHD患者血漿HDL促炎作用中發(fā)揮著重要的作用,同對照組相比,CHD患者血漿HDL能夠顯著地促進(jìn)炎性因子MCP-1的分泌以及VCAM-1和ICAM-1的表達(dá)。用apoCⅢ抗體中和CHD患者血漿HDL組分apoCⅢ的作用能顯著地降低ICAM-1和/或VCAM-1的表達(dá)。3.他汀治療并不能顯著改善CHD患者血漿中HDL的促炎反應(yīng)作用. ApoCⅢ也在他汀藥物治療后CHD患者血漿HDL促炎反應(yīng)中發(fā)揮著重要的作用。小結(jié)1. ApoCⅢ的促炎反應(yīng)呈時間和劑量依賴性。2. ApoCⅢ在CHD患者血漿HDL促炎反應(yīng)中發(fā)揮著重要的作用。3.他汀藥物治療并不能改善CHD患者血漿HDL的促炎反應(yīng)作用,apoCⅢ仍然是他汀藥物治療后CHD患者血漿HDL促炎作用的重要因素。研究總結(jié)(1)血漿HDL組分apoCⅢ的含量和CHD具有正相關(guān)的關(guān)系,是一個較好的CHD預(yù)測指標(biāo)；(2)盡管他汀藥物治療能夠升高HDL-c的水平,但同時也升高了HDL組分apoCⅢ的含量；(3) ApoCⅢ是一個具有促炎作用的載脂蛋白,其促炎作用具有時間和劑量依賴性；(4) ApoCⅢ在CHD患者血漿HDL的促炎反應(yīng)中發(fā)揮著重要的作用；盡管他汀藥物具有一定的抗炎作用,但他汀藥物調(diào)脂治療并不能顯著改善CHD患者血漿HDL的促炎作用,apoCⅢ依然是他汀治療后CHD患者血漿HDL促炎反應(yīng)的重要因素,這可能和他汀藥物治療后HDL組分apoCⅢ含量的升高有關(guān)。(5)本研究進(jìn)一步證實了HDL組分apoCⅢ與HDL生物學(xué)功能和CHD的關(guān)系,為評價HDL生物學(xué)功能和他汀藥物治療效果以及治療和預(yù)防CHD方面提示了一個新的靶點和方向。
[Abstract]:Part 1: the relationship between plasma HDL component apoC III and coronary heart disease and the effect of statin therapy on it, high density lipoprotein (HDL) is the carrier of reverse cholesterol transport (reverse cholesterol transfer, RCT). It is considered as an important protective factor for cardiovascular system. Many epidemiological and clinical studies It has been found and confirmed that coronary heart disease (CHD) has a negative correlation with HDL cholesterol (HDL cholesterol, HDL-c) levels in plasma, but has a positive correlation with low density lipoprotein cholesterol (low density lipoprotein cholesterol) in plasma. Drugs can protect the cardiovascular effect by reducing the level of atherosclerosis and its anti-inflammatory effects in the plasma. As the study continues, it is found that not all CHD patients have low HDL-c levels or high LDL-c levels. In recent years, there has been a gradual research and development, the biological function of HDL and its components. The change is closely related to the pathophysiological state of the body. The development of CHD is related to the changes in some components of HDL, rather than the level of HDL-c in the plasma alone. Recent studies have found that there is a higher level of apolipoprotein C III (apolipoprotein C III, apoC III) in plasma HDL of CHD patients, which can better predict CHD. Development and progress. But due to the general use of statins, the relationship between the content of HDL component apoC III and CHD in plasma and the effects of statins on them are still not very clear. Objective 1. to determine the relationship between the content of apoC III and CHD in plasma HDL components,.2. analysis of the plasma HDL group after the statin treatment of CHD patients The content of apoC III and the changes in the relationship with other blood lipids. 120 patients with CHD and 80 patients with non coronary heart disease, non-CHD were enrolled in the study. All CHD patients received statin therapy and were followed up after 3 months of statin treatment. The patients were collected and followed up. The HDL samples in plasma were extracted by the method of speeding centrifugation. The content of apoC III in plasma and HDL samples was detected by ELISA. The relationship between the content of apoC III and CHD in plasma HDL components and the relationship between the HDL component apoC III of the plasma of CHD patients and the relationship with CHD and blood lipid after treatment with statins were analyzed. The content of HDL component apoC III in plasma of 1.CHD patients was significantly higher than that of non-CHD patients (25.05 + 12.98 g/mgHDL vs 21 + 11.33 g/mgHDL, P0.05), which was statistically significant. Multiple factor risk regression analysis showed that the content of apoCIII in plasma HDL component is still CHD independence after correction of the mixed effects of other risk factors. The risk predictor P0.05).2. statins can significantly reduce the level of TC, LDL-c and apoB in plasma of patients with CHD, and increase the level of HDL-c and apoAI in plasma, but also increase the level of plasma HDL component III (24.26 + 14.80 mu) in CHD patients. Vs 29.35 + 16.46 g/mgHDL, P0.05), there is a significant difference between the plasma HDL component apoC III and the level of TG in plasma of.3. non-CHD patients (R=0.62, P0.05). This correlation is weakened in the plasma of CHD patients (R=0.24,), and the blood is disappearing in the plasma of patients receiving statin treatment. The correlation between the plasma HDL component apoC III and the level of apoC III in plasma was not affected by the state of disease and statins, whether in non-CHD patients (R=0.35, P0.05) or CHD patients (R=0.31, P0.05) and the plasma of CHD patients (R=0.35, P0.05) after statin treatment, we did not find the plasma group. ApoC III was significantly correlated with the level of HDL-c or LDL-c in plasma. The content of HDL component apoC III in plasma of 1.CHD patients was significantly higher than that of non-CHD patients. The content of apoC III in plasma HDL components and CHD had a positive correlation between CHD and.2.,.2. statins therapy could reduce the atherosclerotic blood lipid index and increase the water in the plasma of the CHD patients. Level, but also increased the content of HDL component apoC III in plasma of CHD patients. Second the role of ApoC III in the inflammatory response of human umbilical vein endothelial cells induced by HDL in patients with coronary heart disease and the effect of statin therapy on it, the study of high density lipoprotein (HDL) is not only the reverse transport of cholesterol (reverse cholesterol) (reverse cholesterol) The important carrier of transfer, RCT, can also protect the cardiovascular system through many biological effects such as anti-inflammatory and antioxidant. Many studies have found that the level of HDL in the body is negatively related to the development and development of AS (atherosclerosis, AS) and coronary heart disease (coronary heart disease, CHD), and increases the level of HDL in the plasma. It can reduce the risk of CHD. However, as the study goes deep, it is found that further increasing the level of HDL in plasma of CHD patients does not gain more cardiovascular benefits. The biological effects of HDL are also closely related to the changes in its components and the body's pathophysiology. The plasma of patients with acute stage and end-stage renal disease HDL no longer protects the endothelial cells (endothelial cell, EC), but has a certain role in promoting inflammation, and apoC III in the plasma HDL of CHD patients plays a role in the apoptosis of EC in its plasma HDL. In view of apoC III is a apolipoprotein with proinflammatory activity, it is still not clear that CHD patient plasma HD is still unclear. The elevated apoC III in L also plays a similar role in its plasma HDL proinflammatory response. Statins (statin) drugs have the ability to reduce the level of atheromatous lipids in the plasma, and have some anti-inflammatory effects to protect the cardiovascular system. In view of the changes in the plasma HDL components and their biological functions in the plasma of the CHD patients, But it is not clear whether statin therapy can improve the biological function of plasma HDL in CHD patients. Purpose 1. to study the time and dose dependent.2. study of apoC III proinflammatory response and the role of apoC III in the HDL proinflammatory response in CHD patients.3. to study the effects of statin therapy on the plasma HDL proinflammatory response in patients with coronary heart disease and the effect of statin therapy on the proinflammatory response in patients with coronary heart disease. The role of apoC III in the plasma HDL proinflammatory response in CHD patients after statin treatment. The research method was studied in vitro cultured human umbilical vein endothelial cells (human umbilical venous endothelial cell, HUVEC) as the research object. The simulation of the human environment by using the same dose of apoC III stimulates HUVEC and used different doses of apoC III stimulation. C studied the time and dose dependence of the apoC III pro-inflammatory response. The plasma HDL samples extracted from CHD patients were used to stimulate the effect of HUVEC on the proinflammatory response under the condition of 100 mu g/ml, and then the proinflammatory response after the action of apoC III antibody neutralizing the HDL component apoCIII of CHD patients was explored. By comparing the changes of plasma HDL proinflammatory response in CHD patients before and after statin therapy, the effects of statin therapy on plasma HDL proinflammatory response in patients with CHD were evaluated and the role of apoCIII in the plasma HDL proinflammatory response in CHD patients after statin therapy was explored. Adhesion molecules (vascular cell adhesion molecule 1, VCAM-1), intercellular adhesion molecules (intercellular adhesion molecule 1, ICAM-1), secretion and expression of monocyte chemoattractant protein 1 (monocyte chemotactic protein 1, 6, 6) and other inflammatory factors to evaluate the proinflammatory response. Research results 1. research It is found that the secretion of IL-6 and MCP-1, the increase of the expression of VCAM-1 and ICAM-1, and the increase of.2. apoC III play an important role in the plasma HDL proinflammatory action of CHD patients. Compared with the control group, the plasma HDL of the CHD patient can significantly promote the inflammatory factors than the control group. The secretion of P-1 and the expression of VCAM-1 and ICAM-1. The effect of apoC III antibody and HDL component apoC III in the plasma of CHD patients can significantly reduce the expression of ICAM-1 and / or VCAM-1 in the treatment of.3. statins and does not significantly improve the proinflammatory response of HDL in the plasma of CHD patients. The pro-inflammatory response of 1. ApoC III shows a time and dose dependent.2. ApoC III play an important role in the plasma HDL proinflammatory response of CHD patients..3. statin therapy does not improve the proinflammatory response of HDL in CHD patients. ApoC III is still a HDL proinflammatory effect in the plasma of CHD patients after the statin therapy. Important factors. (1) a positive correlation between the content of apoC III in plasma HDL component and CHD is a good predictor of CHD; (2) although statin therapy can increase the level of HDL-c, it also increases the content of apoC III in the component of HDL; (3) ApoC III is a apolipoprotein with pro-inflammatory effect, and its proinflammatory activity Time and dose dependence; (4) ApoC III plays an important role in the proinflammatory response of HDL in patients with CHD; although statins have certain anti-inflammatory effects, statin therapy does not significantly improve the proinflammatory effect of HDL in plasma of CHD patients, and apoC III is still a plasma HDL proinflammatory reaction in CHD patients after statins treatment. The important factor, which may be related to the increase of apoC III content in HDL component after statin therapy. (5) this study further confirmed the relationship between HDL component apoC III and HDL biological function and CHD, and suggested a new target and direction for evaluating the biological function of HDL and the therapeutic effect of statins, treatment and pre prevention of CHD.

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R541.4

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