【作者】 王萍萍；

【导师】 孔俭；

【作者基本信息】 吉林大学 ， 内科学， 2007， 硕士

【摘要】 动脉粥样硬化所导致的各种心脑血管疾病及其合并症是目前世界范围内(包括我国最新城乡人口死亡情况调查)第二、三位死亡原因,一般认为与目前增多的各种致动脉粥样硬化危险因素有关。目前科学界对动脉粥样硬化发生和发展机制尚无全面深层次的科学解释,因此探讨动脉粥样硬化疾病新机制和新的治疗策略为本研究的主要目的。目前国内外研究认为胰岛素抵抗可能是动脉粥样硬化的核心问题之一。本次研究试用胰岛素增敏剂罗格列酮预防和治疗兔动脉粥样硬化模型,评价其抗动脉粥样硬化作用。将37只健康雄性日本大耳白兔随机分为空白对照组、动脉粥样硬化组、罗格列酮组,于实验第14周末取血测定血脂、血胰岛素、血糖,并处死取主动脉进行病理形态学观察,同时对主动脉及颈动脉组织进行固定、包埋及染色,并行光镜观察。结果表明,罗格列酮组血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)低于动脉粥样硬化组,而高密度脂蛋白胆固醇(HDL-C)明显高于后者(P<0.01)。罗格列酮组主动脉大体标本上粥样硬化病变程度明显较轻,呈不连续片块状,动脉粥样硬化病变面积百分比较动脉粥样硬化组降低59.92%。光镜下罗格列酮组家兔动脉可见内膜、中膜和外膜三层结构,中膜和外膜结构无明显异常,内膜的内皮下可见少量泡沫细胞积聚,形成凸入管腔的局灶性斑块,但斑块面积明显小于动脉粥样硬化组。本研究提示,罗格列酮可以显著抑制动脉粥样硬化病变的发展。更多还原

【Abstract】 At present, with the coming of aging stage, the mortality of cardiovascular and cerebrovascular diseases still keep rising, and play a capital role in the totle one to mankind health. The main pathology foundation of its progress is artherosclerosis. So interfering in artherosclerosis occurrence and development is very important for prevention and cure of cardiovascular and cerebrovascular diseases. It is most important for prevention and cure of cardiovascular and cerebrovascular diseases that we interfere in the progress of artherosclerosis.With the changing of life style and diet structure of modern people, which causes constant rise of diabetes mellitus incidence rate. A great epidemiologic studys show that the mortality and fatality of cardiovascular and cerebrovascular diseases with diabetes is more than without diabetes mellitus. Diabetes mellitus pantients are easier to developing cardiovascular and cerebrovascular diseases than without it, which have been recognized sufficiently.American national cholesterol education programme Adult Treatment Panel III. (NCEP ATPⅢ) have take diabetes mellitus for equal danger to coronary artery disease. Diabetes mellitus earlier period (insulin resistance) can cause endodermis functional disturbance, which may be a important component element. Therefore, the pristine interference of insulin resistance that can prevent and delay the occurrence and development of artherosclerosis leading to cardiovascular and cerebrovascular diseases.As one of insulin sensitizing agents, rosiglitazone is mainly used to cure type 2 diabetes mellitus. The clinical research in last 20 years discovered rosiglitazone could improve blood fat disorder and relieve the development of artherosclerosis. With technology of molecular biology, some researchers got surprising results: peroxisome proliferator-activated receptorγin atherosclerotic plaque and almost all key cells participating the form of artherosclerosis, such as blood vessel endothelium cells, vascular smooth muscle cell and mononuclear macrophage. The results above imply PPARγmay partake in the process of artherosclerosis, and provide us new clues to find more effective medicine for artherosclerosis.Basing on the foundings up to now and experimenting on high fat diet rabbits, our research evaluated influences of rosiglitazone on blood fat disorder, and observed effects of it on the development of artherosclerosis.MethodsWe selected 37 male Japanese albino rabbits, body weight 1.98±0.16kg/each, age 7-8 weeks. All rabbits were randomly divided into three groups: (1) Control group: fed with ordinary fodder 2 times a day; (2) AS group: fed with high fat fodder (120-150g/d) and ordinary fodder; (3) rosiglitazone group: fed with fodder mixed uniformly with rosiglitazone (1.5mg/kg) every morning, then high fat fodder and ordinary fodder. At the beginning of the experiment, we injected the habbits of the last two groups with bovine serum albumin (1g/kg), and the blank group with tales doses of normal saline. The observation time is one week, and the whole experiment time is 14 weeks. At the end of the experiment, we anesthetized rabbits with 10% chloral hydrate, splited the thoracic and abdominal cavity along the anterior median line, and collected the whole blood from heart. We determined immediately TC, TG, HDL-C, LDL-C, FBG, evaluated blood insulin with radio immunoassay and calculated AI and HOMA-IR. Arteriae aorta from aortic root to ambi-iliac arteries was decoherenced and fat stained. We measured the areas of plaque and total endangium, and calculated the proportion of plaque area to the total endangium area. We produced the candle sample with aorta. Then stained them with HE coloring agent. We can observed the thickness of the cellulose of artherosclerosos and the size of the fatnuclear and the tissular change inside plaque.ResultsAt the end of the experiment, the blood serum of control group is light blue color, on the contrary, those of the other two groups are ivory white turbid in different degree. The levels of TC, TG, LDL-C, HDL-C of the rosiglitazone group of high fat diet are predominant higher than those of control group. compared with AS group, the level of HDL-C of rosiglitazone group is 39.69% higher and its levels of TC, TG, LDL-C is lower. There was not visible scleratheroma plaque in control group, and in the arteriae aorta endangium of AS group, we could see large areas of atheromatous plaque generally, and the proportion of plaque area was 74.68±11.89%. What was surprising especially is that the process of artherosclerosis in rosiglitazone group was greatly lessened, and there was only discontinuous scleratheroma plaque. The proportion of plaque area in rosiglitazone group was 29.93±11.54%, which was lower than that of AS group by 59.92%. Through optics camera lens, we can see plenty of froth cells under the artery endothelium in AS group.So it formed partly atheromatous plaque towards the blood vessel`s inside.Compared with AS group, the area of plaque of rosiglitazone group is lessen. Inside of the blood vessel accumulate small amount froth cells.ConclusionWe caused successfully hyperlipemia and artherosclerosis in rabbits by feeding with high fat diet for 14 weeks, which resulted in hyperlipemia in our experiment. We established artherosclerosis model of rabbits in this experiment, and evident scleratheroma plaque was seen in aorta of AS group, what is more, the process of artherosclerosis of roglitazone group was less severe, and concentrated mostly in the beginning of aorta. The proportion of scleratheroma plaque of roglitazone group was lower by 59.92% than that of AS group. It illustrated that roglitazone could obviously restrain uniengulf cell through into endothelium, decrease the number of forth cells. Ultimately it elaborated the function of protecting blood vessel endothelium. The foundings above certificated roglitazone could actively inhibit the development of artherosclerosis. At the same time, we found rosiglitazone lowered TC, TG, LDL-C a little, and what was the most important was this insulin sensitizer could remarkably raise HDL-C up. Rosiglitazone effectively accommodated blood fat disorder, and this condition was nonadvantageous for the formation of artherosclerosis.更多还原