【作者】 杜瑞雪；

【导师】 叶平；

【作者基本信息】 中国人民解放军军医进修学院 ， 老年心血管病， 2010， 博士

【摘要】 背景和目的：动脉粥样硬化(AS)是缺血性心脑血管疾病的主要病理生理基础。他汀类药物具有显著的抗AS作用。临床方面,ASTEROID研究显示他汀治疗2年能引起粥样硬化斑块的逆转,但近期小样本研究显示,他汀短期内有可能缩小斑块。在细胞和分子水平,基础研究显示,调脂外的抗炎作用,是他汀抗AS的另一重要环节。而且,其上游途径可能有PPARs通路参与,但具体机制不清。本研究旨在：1.应用高分辨率MRI观察瑞舒伐他汀对颈动脉粥样硬化斑块的短期疗效；2.观察瑞舒伐他汀对相关炎症因子的作用；3.初步探讨瑞舒伐他汀对PPARs途径的影响。方法：1.入选年龄18-75岁,LDL-C 2.6mmol/L-6.5mmol/L;甘油三酯≤4.0mmol／L,有颈动脉粥样硬化斑块,从未使用过他汀类药物的患者20例,瑞舒伐他汀5-20mg／日治疗3月,应用高分辨率MRI检测治疗后斑块、脂核的体积变化,分析其与血脂相关性。2.常规检测血清hsCRP，ELISA法检测血浆MCP-1、VCAM-1水平,荧光定量RT-PCR检测单个核细胞ICAM-1、CCR2的mRNA水平,流式细胞学检测其表达。3.荧光定量RT-PCR检测单个核细胞PPARα、β、γ的mRNA水平,Western blot检测其核内活化蛋白表达。结果：1.与基线时比较,瑞舒伐他汀治疗后LDL-C、TC、TG水平降低(P<0.05), HDL-C升高不明显(P>0.05)；颈动脉斑块体积、脂核体积均较前缩小。脂核减少的程度和LDL-C减少的幅度成正相关；斑块体积减少的程度与LDL-C、TC减少的幅度均成正相关。2.瑞舒伐他汀治疗降低患者血中hsCRP、MCP-1的水平(P<0.05),减少单个核细胞CCR2及淋巴细胞表面ICAM-1的表达,对血浆VCAM-1水平及单核细胞表面ICAM-1的表达无影响。3.瑞舒伐他汀增加单个核细胞PPARα、β的mRNA水平,对PPARγmRNA表达无明显影响；Western blot结果显示,瑞舒伐他汀治疗后三种PPAR的核内活化蛋白均增加(P<0.05)。结论：1.瑞舒伐他汀具有良好的降脂作用,短期内即可缩小颈动脉粥样硬化斑块,减小脂核,起到稳定斑块的作用。2.瑞舒伐他汀通过减少单个核细胞的相关粘附分子和趋化因子发挥抗炎抗AS作用。3.瑞舒伐他汀抗动脉粥样硬化作用可能与上调单个核细胞PPARs有关,但尚需进一步研究证明。本研究为探讨瑞舒伐他汀的抗动脉粥样硬化机制提供了理论依据。更多还原

【Abstract】 Objective:Atherosclerosis is the cause of ischemic cerebrovascular disease in pathophysiology. Statins have a significant benifet on prevention and treatment of atherosclerosis.ASTEROID research showed that statin therapy can reverse atherosclerotic plaques. Othervise, recent research from small samples showed that rosuvastatin may regress atherosclerotic plaques in only 1 to 3 months. Other research showed that anti-inflammatory effects of statin beside lipid-lowering,mostly in vitro, is equally important to retarding atherosclerosis. PPARs, which regulate lipid metabolism and inflammatory, probably invlved in the effects of rosuvastatin on atherosclerosis. The purposes of this study were:1. To observe the effects of rosuvastatin on carotid atherosclerotic plaque with high-resolution MRI; 2. to investigate the effects of rosuvastatin on inflammatory factors; 3. to study the relation of rosuvastatin and PPARs.Methods:1.20 patients without previous statin treatment were enrolled, with age 18 to 75 years-old, LDL-C 2.6mmol/L to 6.5mmol/L, triglyceride less than 4.0mmol/L, coratid plaques with lipid core. Rosuvastatin were given 5 to 20mg/day for 3 months. Both plaque and lipid core volume were examined with high-resolution MRI after rosuvastatin treatment and their correlation were analyzed.2. The levels of hsCRP, MCP-1 and VCAM-1 were examined in serum or plasma. The mRNA and protein expression of ICAM-1 and CCR2 were measured with RT-PCR and flow cytometry, respectively.3. The mRNA and protein expression of PPARs were detected with RT-PCR and Western blot.Result:1.Compared with the baseline, the levels of LDL-C, TC and TG were decreased after rosuvastatin treatment (P< 0.05). The levels of HDL-C is little higher with no significant (P> 0.05). Both volumes of carotid artery plaques and lipid core were decreased. The correlation between change of lipid core volume and LDL-C decrease was present as well as the reduction of the plaque volume and LDL-C, TC decrease.2. Rosuvastatin reduced hsCRP and MCP-1 levels(P< 0.05), CCR2 expression on mononuclear cells and ICAM-1 expression on lymphocyts. The effects of rosuvastatin on VCAM-1 level and ICAM-1 expression on monocyte was not be observed.3. Rosuvastatin improve mRNA and protein expression of PPARa andβ, also increase PPARy protein expression. Otherwise, its effect on PPARy mRNA expression was not significant.Conclusion:1. The study showed obviously improve on blood lipid profile by rosuvastatin. Regression of atherosclerotic plaques and lipid core also were observed in a short term, which may helpful to plaque stabilization.2. Rosuvastatin exert anti-inflammatory effects through decreasing some adhesion molecules and chemokine on mononuclear cells.3. Upregulation of PPARs levels may relate to the anti-atherosclerosis mechanisms of statin, although further study should be needed. This study may be helpful to further explore rosuvastatin anti-atherosclerosis.更多还原