脂脉康对高血脂致动脉粥样硬化的保护作用及其机制的实验研究

【作者】 庞剑；

【导师】 周学文；

【作者基本信息】 辽宁中医学院 ， 中医基础理论， 2004， 博士

【摘要】 背景：高血脂又称脂代谢紊乱或血脂异常。近年来呈低龄发病的趋势。关于血脂异常的研究已在国内外引起高度重视，高脂血症是致动脉粥样硬化的危险因子，是冠心病、高血压、脑卒中、老年痴呆的重要危险因素，流行病学调查显示我国人群的血脂平均水平和血脂异常的患病率无论城乡、南北正在迅速上升，其中在经济发达地区已达到较高水平，并已把对血脂异常潜在危险的研究从对冠心病单一疾病的评价发展到对冠心病、脑卒中、恶性肿瘤、总死亡等多种健康结局的评价。西医学认为高脂血症病因复杂，治疗较为困难，目前药物和治疗方法疗效并不理想，即使有效，停药后血脂水平即回到用药前，并且有效的降脂药物存在一定的副作用，因此高脂血症的现代医学治疗是一个长期的、相当费钱的、并有一定安全风险的任务。中药对高血脂的治疗和预防均有良好的效果，且副作用小，开发具有独立知识产权、治疗血脂异常的中药复方制剂已迫在眉睫。寻找有效的药物防止、延缓和逆转动脉粥样硬化是一个重要医学课题，是防治心脑血管疾病的重要基础。 目的：通过建立新西兰家兔高脂血症模型，探讨高血脂与动脉粥样硬化的关系；从三个不同的角度观察脂脉康对血脂及动脉粥样硬化的影响，并探讨脂脉康降低血脂，抑制动脉粥样硬化的机理，并同血脂康、辛伐他汀进行比较，为脂脉康在临床的进一步应用提供理论依据。 方法：1、通过喂饲高脂饲料，造成高脂血症动物模型。2、通过生化、放免检测，从血管活性物质方面探讨脂脉康对内皮功能的影响。3、应用免疫组化、RT-PCR方法分别对颈动脉、主动脉进行血管细胞粘附分子-1的检测。4、应用光镜及透射电镜观察颈动脉的超微结构变化。5、通过颈动脉彩超观察颈动脉斑块的形成。6、应用BT-3型实验性体内血栓形成测定仪，观察颈动脉血栓形成时间。 结果：通过喂饲高脂饲料，成功造成高脂血症动物模型。高脂血症模型对照组血脂谱TC、TG、LDL-C均明显升高，HDL-C明显降低，ET与NO、TXB₂与6-K-PGF1_a平衡失调，血液粘滞度增高，纤溶功能受损，血管内皮功能障碍，动脉粥样硬化形成。大剂量脂脉康可明显降低TC、TG、LDL-C水平，升高HDL-C水平，纠正ET与NO、TXB₂与6-K-PGF1_a平衡失调，免疫组化、RT-PCR显示颈动脉、主动脉血管细胞粘附分子-1表达降低，同时可提高纤溶活性，降低血液粘滞度，延长血栓形成时间，改善动脉粥样硬化病理变化。同西药对照组（辛伐他汀）对比疗效相当，但无肌病（横纹肌溶解）及肝损害等临床上难以预测的严重不良反应。 结论：脂脉康通过降低血脂，减少脂代谢异常对血管壁内皮细胞结构和功能的损害，恢复血管内皮功能，防止炎性细胞粘附，抑制平滑肌细胞增殖和迁移，减少细胞外基质辽宁中医学院博士学位论文产生，有效的降低血脂后，血管内皮局部凝血、纤溶系统功能紊乱状况有所改善，进而稳定斑块，防止破裂，防止血小板粘附和血栓形成，最终使动脉粥样硬化发生和发展受到抑制并缓解。更多还原

【Abstract】 Background: Hyperlipidaemia, also called as dyslipidaemia, is a disorder of lipid metabolism. In recent years, a tendency of hyperlipidaemia is its early onset in young people. Hyperlipidaemia is an important risk factor for atherosclerosis, as well as for angina pectoris, hypertension, stroke, and vascular dementia, therefore, research works on dyslipidaemia has been drawing lots of attentions both from domestic and from abroad. Epidemiology researches showed a rapid increase of average blood-lipid level as well as a climbing incidence of dyslipidaemia in the populations of our nation, regardless of the differences between city and country, north and south. Especially in the economically developed region, highest blood-lipid was observed. Furthermore, the potential risk assessment of dyslipidaemia has been developed from for a single cardiovascular disease into a overall assessment for multiple health prognoses including cardiovascular disease, stroke, malignancies, and total mortalities. In Western medicine, hyperlipidaemia is regarded as a complicated disease with great difficulties in treatment, most of the current medicines and therapies have no a ideal curative effect, and even some of them may have partial effects, the blood-lipid level would go back to the pretreatment level after medicine withdraw, moreover, side effects are always accompanied with these medicines. Thus, modern medical treatment of hyperlipidaemia is a costly long-term task with a certain risks. Chinese medicine has been shown outstanding effectiveness in both treatment and prevention of hyperlipidaemia with few side effects. Therefore, the development of a traditional compound preparation for hyperlipidaemia with independent intellectual asset is of great imminent significance. Figuring out potent traditional medicine to postpone, prevent, and even reverse the progress of atherosclerosis is an important medical project, and will serve as the crucial groundwork in the prevention and treatment of cardiac cerebral vascular diseases.Objectives: Using hyperlipidaemia model of New Zealand rabbit, to explore the relationships between hyperlipidaemia and atherosclerosis; Observing the anti-hyperlipidaemia and anti-atherosclerosis effects of ZHI-MAI-KANG compound preparation fromthree individual aspects, and further study its corresponding mechanisms, the effects of ZHI-MAI-KANG will be compared with those of XUE-ZHI-KANG and Simvastatin, and thus it will provid theoretical basis for the clinical application of ZHI-MAI-KANG.Methods: 1. hyperlipidaemia model was established using high-fat diet. 2. The effects of ZHI-MAI-KANG on the functions of endothelium of vascular were studied through biochemical and immunoradioactive assays, including endothelin (ET), thromboxane B2 (TXB2), 6-keto-prostaglandin Fl alpha (6-K-PGFla), lipid peroxidation (LPO), superoxide dismutase(SOD), and Nitric Oxide (NO). 3. The expression of vascular cell adhesion molecule-1 (VCAM-l) in the carotid and aortic arteries was determined using immunochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). 4. The micro and ultra-structure of carotid artery were observed employing optical and transmission electron microscopes. 5. The formation of atheromatous plaque on the endothelium of carotid artery was detected using colour doppler sonography. 6. The activated partial thromboplastin time was measured using BT-3 type experimental in vivo thrombosis detection apparatus.Results:A hyperlipidaemia model was successfully established using high-fat diet in New Zealand rabbits. In the hyperlipidaemia positive control group, the level of total cholesterol (TC), total glycerol (TG), and low density lipid protein-C (LDL-C) were significantly elevated, the level of high density lipid protein (HDL) was significantly decreased. The imbalances between ET and NO, TXB2 and 6-K-PGFloc were observed. Viscosity of blood was increased, fibrinolysis function was impaired, accompanied by vascular endothelium disfuntion and the formation of artery atherosclerosis. High dose更多还原