血聚HDL组分apoCⅢ与冠心病及其HDL促炎反应的关系以及他汀治疗对其影响

发布时间：2018-04-20 11:00

本文选题：冠心病 + 高密度脂蛋白　；参考：《北京协和医学院》2016年博士论文

【摘要】：第一部分血浆HDL组分apoCⅢ与冠心病的关系及他汀治疗对其影响研究背景高密度脂蛋白(high density lipoprotein, HDL)作为胆固醇逆向转运(reverse cholesterol transfer, RCT)的载体,被认为是心血管系统重要的保护因子。众多的流行病学和临床研究已经发现并证实了冠心病(coronary heart disease, CHD)和血浆中HDL胆固醇(HDL cholesterol, HDL-c)水平具有负相关、而和血浆中低密度脂蛋白胆固醇(low density lipoprotein cholesterol, LDL-c)具有正相关的关系。作为一类有效的调脂药物,他汀类(statin)药物则能通过降低血浆中致粥样硬化脂质的水平和其抗炎作用发挥保护心血管的作用。随着研究的不断深入,人们发现并非所有的CHD患者都存在低HDL-c水平或高LDL-c水平的情况。近年来逐渐有研究发现,HDL的生物学功能和其自身组分的变化以及机体的病理生理状态密切相关,CHD的发生发展也与HDL中一些组分的变化相关,而非单纯地和血浆中HDL-c的水平相关。最近的研究发现,CHD患者血浆HDL中存在较高的载脂蛋白CⅢ (apolipoprotein CⅢ, apoCⅢ)水平,其能够更好地预测CHD的发生和进展。但由于他汀药物的普遍应用,血浆HDL组分apoCⅢ的含量与CHD的关系以及他汀类药物治疗后对它们的影响目前仍不十分清楚。研究目的1.明确血浆HDL组分apoCⅢ的含量和CHD的关系。2.分析研究CHD患者他汀药物治疗后血浆HDL组分apoCⅢ的含量及其与其它血脂关系的变化。研究方法入选经冠脉造影确诊的CHD患者120例和非冠心病(non coronary heart disease, non-CHD)患者80例。所有CHD患者均接受他汀药物治疗,并在他汀治疗3个月后接受随访。收集入选患者以及随访患者的临床资料并采集空腹静脉血,采用超速离心的方法提取血浆中HDL样品,应用ELISA的方法检测血浆和HDL样品中apoCⅢ的含量。统计学分析血浆HDL组分apoCⅢ的含量与CHD的关系以及他汀治疗后对CHD患者血浆HDL组分apoCⅢ及其与CHD和血脂关系的影响。研究结果1.CHD患者血浆HDL组分apoCⅢ的含量显著高于non-CHD患者(25.05±12.98μg/mgHDL vs 21.00±11.33 μg/mgHDL,p0.05),具有统计学意义。多因素风险回归分析显示,在校正了其它危险因素的混杂影响后,血浆HDL组分apoCIII的含量依然是CHD独立的风险预测因子p0.05)。2.他汀药物治疗能够显著地降低CHD患者血浆中TC、LDL-c和apoB等致粥样硬化血脂的水平p0.001),并升高血浆中HDL-c和apoAI等抗粥样硬化血脂的水平p0.001),但同时也升高了CHD患者血浆HDL组分apoCⅢ的含量(24.26±14.80 μg/mgHDL vs 29.35±16.46μg/mgHDL,p0.05),差异具有统计学意义。3. non-CHD患者血浆HDL组分apoCⅢ和血浆中TG的水平具有显著的正相关关系(R=0.62,p0.05),这种相关性在CHD患者血浆中减弱(R=0.24,p0.05),并在接受他汀治疗后的CHD患者血浆中消失(R=0.11,p0.05)。而血浆HDL组分apoCⅢ和血浆中apoCⅢ水平之间的相关性并不受疾病状态和他汀药物的影响,无论是在non-CHD患者(R=0.35,p0.05)还是CHD患者(R=0.31,p0.05)以及他汀药物治疗后的CHD患者(R=0.35,p0.05)血浆中均有相关性。4.本研究中,我们并未发现血浆HDL组分apoCⅢ与血浆中HDL-c或LDL-c的水平具有明显的相关性。小结1.CHD患者血浆HDL组分apoCⅢ的含量显著高于non-CHD患者,血浆HDL组分apoCⅢ的含量和CHD之间具有正相关的关系。2.他汀治疗能降低CHD患者血浆中致粥样硬化血脂指标和升高HDL-c的水平,但同时也升高了CHD患者血浆中HDL组分apoCⅢ的含量。第二部分ApoCⅢ在冠心病患者HDL促人脐静脉内皮细胞炎症反应中的作用及他汀治疗对其影响研究背景高密度脂蛋白(high density lipoprotein, HDL)不仅是胆固醇逆向转运(reverse cholesterol transfer, RCT)的重要载体,其也能通过抗炎抗氧化等多种生物学效应发挥对心血管系统的保护作用。众多研究发现,体内的HDL水平与AS(atherosclerosis, AS)和冠心病(coronary heart disease, CHD)的发生和发展具有负相关的关系,升高血浆中HDL的水平能够降低CHD的发病风险。然而随着研究的深入,人们发现,进一步升高CHD患者血浆中HDL的水平并不能得到更多的心血管获益,HDL的生物学作用也和其组分改变以及机体的病理生理状态密切相关。急性期反应阶段和终末期肾病患者血浆中的HDL对内皮细胞(endothelial cell, EC)不再具有保护作用,反而具有一定的促进炎症反应的作用,而CHD患者血浆HDL中升高的apoCⅢ在其血浆HDL促进EC的凋亡中发挥着作用。鉴于apoCⅢ是一种具有促炎作用的载脂蛋白,目前仍不清楚CHD患者血浆HDL中升高的apoCⅢ在其血浆HDL促炎反应中是否也发挥着类似的作用。他汀类(statin)药物处了能够降低血浆中致粥样硬化脂质的水平外,其还有一定的抗炎作用,从而发挥保护心血管的作用。鉴于CHD患者血浆HDL组分及其生物学功能的改变,但目前并不清楚他汀药物治疗是否能够改善CHD患者血浆HDL的生物学功能。研究目的1.研究apoCⅢ促炎反应的时间和剂量依赖性。2.研究apoCⅢ在CHD患者HDL促炎反应中的作用。3.研究他汀药物治疗后对冠心病患者血浆HDL促炎反应的影响以及apoCⅢ在他汀治疗后CHD患者血浆HDL促炎反应中的作用。研究方法以体外培养的人脐静脉内皮细胞(human umbilical venous endothelial cell, HUVEC)为研究对象,模拟人体环境利用同一剂量的apoCⅢ刺激HUVEC不同的时间和利用不同剂量的apoCⅢ刺激HUVEC研究apoCⅢ促炎反应的时间和剂量依赖性。并利用提取的CHD患者血浆HDL样品在100μg/ml的条件下刺激HUVEC评价其促炎反应的作用,然后利用apoCⅢ抗体中和CHD患者血浆HDL组分apoCIII的作用后促炎反应的变化探索apoCIII在CHD患者血浆HDL促炎反应中的作用。通过比较他汀药物治疗前后CHD患者血浆HDL促炎反应的变化评价他汀治疗对CHD患者血浆HDL促炎反应的影响,并利用抗体中和的方法探索apoCIII在他汀治疗后CHD患者血浆HDL促炎反应中的作用。本部分研究中,我们以血管细胞黏附分子(vascular cell adhesion molecule 1, VCAM-1),细胞间黏附分子(intercellular adhesion molecule 1, ICAM-1),单核细胞趋化蛋白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达来评价促炎反应情况。研究结果1.研究发现,随着apoCⅢ作用于HUVEC浓度的增加或时间的延长,炎性因子IL-6和MCP-1的分泌以及VCAM-1和ICAM-1的表达逐渐增多和增加。2. apoCⅢ在CHD患者血浆HDL促炎作用中发挥着重要的作用,同对照组相比,CHD患者血浆HDL能够显著地促进炎性因子MCP-1的分泌以及VCAM-1和ICAM-1的表达。用apoCⅢ抗体中和CHD患者血浆HDL组分apoCⅢ的作用能显著地降低ICAM-1和/或VCAM-1的表达。3.他汀治疗并不能显著改善CHD患者血浆中HDL的促炎反应作用. ApoCⅢ也在他汀药物治疗后CHD患者血浆HDL促炎反应中发挥着重要的作用。小结1. ApoCⅢ的促炎反应呈时间和剂量依赖性。2. ApoCⅢ在CHD患者血浆HDL促炎反应中发挥着重要的作用。3.他汀药物治疗并不能改善CHD患者血浆HDL的促炎反应作用,apoCⅢ仍然是他汀药物治疗后CHD患者血浆HDL促炎作用的重要因素。研究总结(1)血浆HDL组分apoCⅢ的含量和CHD具有正相关的关系,是一个较好的CHD预测指标；(2)尽管他汀药物治疗能够升高HDL-c的水平,但同时也升高了HDL组分apoCⅢ的含量；(3) ApoCⅢ是一个具有促炎作用的载脂蛋白,其促炎作用具有时间和剂量依赖性；(4) ApoCⅢ在CHD患者血浆HDL的促炎反应中发挥着重要的作用；尽管他汀药物具有一定的抗炎作用,但他汀药物调脂治疗并不能显著改善CHD患者血浆HDL的促炎作用,apoCⅢ依然是他汀治疗后CHD患者血浆HDL促炎反应的重要因素,这可能和他汀药物治疗后HDL组分apoCⅢ含量的升高有关。(5)本研究进一步证实了HDL组分apoCⅢ与HDL生物学功能和CHD的关系,为评价HDL生物学功能和他汀药物治疗效果以及治疗和预防CHD方面提示了一个新的靶点和方向。
[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.

【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R541.4

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