环糊精延缓动脉粥样硬化形成的作用及其机制研究
发布时间：2018-11-26 17:29
【摘要】：环糊精作为药物载体在药物学方面被广泛应用,最近几年作为药物用于治疗C型尼曼匹克氏等特殊疾病。由于环糊精“腔内疏水,腔外亲水”独特立体结构,环糊精具备剔除脂蛋白复合分子中或活细胞表面脂质分子的能力,尤其是胆固醇。多种血浆脂蛋白和细胞被证实参与动脉粥样硬化的形成与发展,其中低密度脂蛋白胆固醇水平与氧化型低密度脂蛋白浓度是诱发该疾病的关键因素。鉴于环糊精特性与动脉粥样硬化诱因之间的关联,我们推测环糊精可以剔除血浆脂蛋白与动脉粥样硬化形成相关细胞表面的胆固醇等脂质分子,改变其结构、性质或功能,最终影响动脉粥样硬化的形成与发展。本课题旨在验证此推测,揭示环糊精抗动脉粥样硬化的作用及其潜在机制。为揭示环糊精抗动脉粥样硬化的作用,选择ApoE-/-小鼠为模型小鼠,以2-羟丙基-β-环糊精为代表,进行动物实验,结果表明:环糊精能显著降低血清甘油三酯含量、降低ox-LDL水平、减少血管脂质斑块量等,最终有效缓解动脉粥样硬化的病发进程。为探讨环糊精延缓动脉粥样硬化的可能机制,检测不同种类不同浓度环糊精对血液主要脂蛋白LDL与HDL的结构与体外氧化影响及原因,结果显示环糊精能剔除这两者的部分脂类成分,能抑制这两类脂蛋白的氧化,抑制效果呈浓度依赖性,揭示环糊精延缓AS的可能机制1:环糊精影响LDL结构成分并抑制其氧化;可能机制2:环糊精影响HDL的成分并抑制其氧化。为进一步探讨作用机制,设计细胞与分子实验,检测环糊精对单核细胞与血管内皮细胞之间粘附作用的影响及机制,结果表明环糊精通过影响黏附分子ICAM-1、VCAM、E-Selectin的分泌、细胞骨架及其相关分子,显著抑制单核细胞THP-1与内皮细胞HUVEC的黏附,后者是动脉粥样硬化形成的关键步骤,这揭示了环糊精延缓AS的可能机制3:环糊精能减少内皮细胞黏附分子的分泌等,抑制单核细胞与内皮细胞的黏附。总而言之,本论文明确了环糊精抗动脉粥样硬化的作用。由于动脉粥样硬化的诱发因素复杂多样,故环糊精抗动脉粥样硬化的几种机制可能会相互干扰或影响,或许会如同文中所描述那样错综复杂。本研究不仅为动脉粥样硬化的预防或治疗提供了一种可能的新药或新方向,而且让具备促溶、低毒、安全等优点的环糊精在生物医药领域中的应用被拓展升华。
[Abstract]:Cyclodextrins have been widely used in pharmacology as drug carriers and in recent years as drugs for the treatment of specific diseases such as type C Neimanpik's. Due to the unique three-dimensional structure of cyclodextrin, especially cholesterol, cyclodextrin has the ability to remove lipids from lipoprotein complex molecules or living cell surface. A variety of plasma lipoproteins and cells have been proved to be involved in the formation and development of atherosclerosis, among which the level of low density lipoprotein cholesterol and the concentration of oxidized low density lipoprotein are the key factors to induce the disease. In view of the correlation between cyclodextrin properties and the causes of atherosclerosis, we speculate that cyclodextrin can remove lipid molecules such as cholesterol on the surface of cells associated with atherosclerosis and alter their structure, properties or functions. Ultimately affect the formation and development of atherosclerosis. The aim of this study was to verify this hypothesis and to reveal the anti-atherosclerotic effect of cyclodextrin and its underlying mechanism. In order to reveal the anti-atherosclerosis effect of cyclodextrin, ApoE-/- mice were selected as model mice and 2-hydroxypropyl- 尾 -cyclodextrin was used as the representative in animal experiments. The results showed that cyclodextrin could significantly reduce serum triglyceride content. Reduce the level of ox-LDL, reduce the amount of vascular lipid plaque, and ultimately alleviate the progression of atherosclerosis. In order to explore the possible mechanism of cyclodextrin delaying atherosclerosis, the effects of different kinds of cyclodextrins on the structure and in vitro oxidation of main lipoprotein LDL and HDL were detected. The results showed that cyclodextrin could remove some of the lipids and inhibit the oxidation of these two lipoproteins in a concentration-dependent manner. The possible mechanism of cyclodextrin delaying AS was 1: cyclodextrin affected the structural components of LDL and inhibited its oxidation. Mechanism 2: cyclodextrin affects the composition of HDL and inhibits its oxidation. In order to further explore the mechanism, cell and molecular experiments were designed to detect the effect and mechanism of cyclodextrin on adhesion between monocytes and vascular endothelial cells. The results showed that cyclodextrin affected the adhesion molecule ICAM-1,VCAM, by the effect of cyclodextrin on the adhesion between monocytes and vascular endothelial cells. The secretion of E-Selectin, cytoskeleton and its associated molecules significantly inhibit the adhesion of monocyte THP-1 to endothelial cell HUVEC, which is a key step in the formation of atherosclerosis. This reveals the possible mechanism of cyclodextrin delaying AS 3: cyclodextrin can reduce the secretion of endothelial cell adhesion molecules and inhibit the adhesion of monocytes to endothelial cells. All in all, the effect of cyclodextrin on atherosclerosis is clarified. Several mechanisms of cyclodextrin anti-atherosclerosis may interfere or affect each other because of the complexity of the inducing factors of atherosclerosis, and may be as complicated as described in this paper. This study not only provides a possible new drug or new direction for the prevention or treatment of atherosclerosis, but also expands the application of cyclodextrin in biomedical field with the advantages of promoting dissolution, low toxicity and safety.
【学位授予单位】：南昌大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R96
[Abstract]:Cyclodextrins have been widely used in pharmacology as drug carriers and in recent years as drugs for the treatment of specific diseases such as type C Neimanpik's. Due to the unique three-dimensional structure of cyclodextrin, especially cholesterol, cyclodextrin has the ability to remove lipids from lipoprotein complex molecules or living cell surface. A variety of plasma lipoproteins and cells have been proved to be involved in the formation and development of atherosclerosis, among which the level of low density lipoprotein cholesterol and the concentration of oxidized low density lipoprotein are the key factors to induce the disease. In view of the correlation between cyclodextrin properties and the causes of atherosclerosis, we speculate that cyclodextrin can remove lipid molecules such as cholesterol on the surface of cells associated with atherosclerosis and alter their structure, properties or functions. Ultimately affect the formation and development of atherosclerosis. The aim of this study was to verify this hypothesis and to reveal the anti-atherosclerotic effect of cyclodextrin and its underlying mechanism. In order to reveal the anti-atherosclerosis effect of cyclodextrin, ApoE-/- mice were selected as model mice and 2-hydroxypropyl- 尾 -cyclodextrin was used as the representative in animal experiments. The results showed that cyclodextrin could significantly reduce serum triglyceride content. Reduce the level of ox-LDL, reduce the amount of vascular lipid plaque, and ultimately alleviate the progression of atherosclerosis. In order to explore the possible mechanism of cyclodextrin delaying atherosclerosis, the effects of different kinds of cyclodextrins on the structure and in vitro oxidation of main lipoprotein LDL and HDL were detected. The results showed that cyclodextrin could remove some of the lipids and inhibit the oxidation of these two lipoproteins in a concentration-dependent manner. The possible mechanism of cyclodextrin delaying AS was 1: cyclodextrin affected the structural components of LDL and inhibited its oxidation. Mechanism 2: cyclodextrin affects the composition of HDL and inhibits its oxidation. In order to further explore the mechanism, cell and molecular experiments were designed to detect the effect and mechanism of cyclodextrin on adhesion between monocytes and vascular endothelial cells. The results showed that cyclodextrin affected the adhesion molecule ICAM-1,VCAM, by the effect of cyclodextrin on the adhesion between monocytes and vascular endothelial cells. The secretion of E-Selectin, cytoskeleton and its associated molecules significantly inhibit the adhesion of monocyte THP-1 to endothelial cell HUVEC, which is a key step in the formation of atherosclerosis. This reveals the possible mechanism of cyclodextrin delaying AS 3: cyclodextrin can reduce the secretion of endothelial cell adhesion molecules and inhibit the adhesion of monocytes to endothelial cells. All in all, the effect of cyclodextrin on atherosclerosis is clarified. Several mechanisms of cyclodextrin anti-atherosclerosis may interfere or affect each other because of the complexity of the inducing factors of atherosclerosis, and may be as complicated as described in this paper. This study not only provides a possible new drug or new direction for the prevention or treatment of atherosclerosis, but also expands the application of cyclodextrin in biomedical field with the advantages of promoting dissolution, low toxicity and safety.
【学位授予单位】：南昌大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R96
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