【作者】 崔颖；

【导师】 牛楠；

【作者基本信息】 大连医科大学 ， 内科学， 2007， 硕士

【摘要】 背景与目的动脉粥样硬化被认为是一种慢性炎症性疾病,过氧化物酶体增殖体激活受体(PPARγ)是对机体代谢过程起重要调节作用的一种核激素受体,研究表明PPARγ活化能抑制炎症反应而对动脉粥样硬化产生影响。他汀类药物通过有效的降低LDL在冠心病治疗中占有重要的地位,目前研究发现其抗动脉粥样硬化的作用还得益于调脂以外的非调脂尤其是抗炎作用,其机制尚未完全明确,我们推测这种抗炎作用部分是通过激活PPARγ介导的。方法入选2006年7月至2006年12月在大连医科大学附属第二医院心内科病房住院病人159例,包括正常对照组35例和急性冠脉综合征组(ACS组)124例,ACS组又分为不稳定型心绞痛组(UA组)和急性心肌梗死组(AMI组)。ACS组患者在常规药物治疗(抗凝,硝酸脂类,β受体阻滞剂,血管紧张素转换酶抑制剂和钙拮抗剂等)基础上随机给予阿托伐他汀(Statin)10mg,每晚一次(10mg组)和阿托伐他汀40mg,每晚一次(40mg组)。分别于药物治疗前,用药一周采空腹静脉血,用流式细胞术检测各组入选者外周血单核细胞中PPARγ蛋白的表达,采用荧光免疫法检测外周血单核细胞中PPARγ的荧光强度的表达,同时常规查HsCRP,血脂,血糖,肾功,离子。分离正常组单核细胞,体外干预分为对照组,LPS组(脂多糖),LPS+Statin组, LPS+Statin+MVA(甲羟戊酸)组,刺激24小时后收集单核细胞,采用RT-PCR技术检测单核细胞中PPARγmRNA的表达。结果正常人及急性冠脉综合征患者外周血单核细胞均可见PPARγ的表达,急性冠脉综合征患者HsCRP(超敏C反应蛋白)水平较正常对照组升高(8.07±0.51 vs 2.99±0.15mg/L, p<0.05),而外周血单核细胞中PPARγ的表达较正常对照组降低(1.15±0.43 vs 5.93±0.54, p<0.05)。急性冠脉综合征患者中急性心肌梗死患者PPARγ的表达较不稳定型心绞痛明显降低(0.51±0.42 vs 3.13±0.88 ,P<0.01),HsCRP水平较UA组患者明显升高(16.07±0.86 vs 5.21±0.72mg/L, p<0.01)。短期内应用阿托伐他汀后,急性冠脉综合征患者中40mg组治疗前后升高PPARγ及降低HsCRP的幅度均较10mg组更明显(PPARγ:3.38±0.12 vs 0.51±0.02 ,P<0.01;HsCRP:11.45±2.14 vs 1.00±2.25mg/L, p<0.01)。体外药物干预正常人外周血单核细胞,给予阿托伐他汀及LPS刺激24小时后,PPARγmRNA的表达较单纯LPS组明显升高(0.68±0.17 vs 0.56±0.02, p <0.01),再给予甲羟戊酸后PPARγmRNA的表达又较LPS+Statin组减弱(0.58±0.12 vs 0.68±0.17,p<0.01),推测阿托伐他汀可能通过甲羟戊酸途径影响核受体PPARγ的表达。结论1.正常人及急性冠脉综合征患者外周血单核细胞中均有PPARγ的表达,急性冠脉综合征患者较正常人PPARγ的表达明显降低。2.随着ACS病情加重PPARγ的表达进一步下降。3.阿托伐他汀能够改善急性冠脉综合征PPARγ的表达,40mg较10mg组效果明显。阿托伐他汀可能通过甲羟戊酸途径影响核受体PPARγ的表达。4.阿托伐他汀能够降低ACS患者外周血血清HsCRP的浓度,说明它具有抗炎作用,其抗炎作用可能与其改善PPARγ表达有关。更多还原

【Abstract】 Background and Objective It is widely recognized that atherosclerosis is a specific example of a chronic inflammatory disease. Peroxisome Proliferator Activated Receptor Gamma (PPARγ) is a kind of nuclear hormone receptor,which play most important roles in regulation of metablism. Some studies indicated that activation of PPARγcould lead to reduction in atherosclerosis by decreasing inflammatory responses. Anti-inflammatory effects of statins contribute to their clinical benefit. Molecular mechanisms underlying these effects have not been well explored. We hypothesized that part of this anti-inflammation effects are mediated by activation of PPARγ.Methods 159 persons (35 normal persons and 124 patients with ACS) were investigated. Patients with ACS were randomized to either atorvastatin 10mg/d or atorvastatin 40mg/d in addition to their routine anti-anginal treatment. Serum level of HsCRP, blood lipids and expression of PPARγin peripheral blood monocytes were measured before and after one week treatment.Expression of PPARγwere quantified via flow-cytometry. PPARγexpression in monocytes after incubation with atorvastatin for 24 hours were quantitative via RT-PCR.Results Our studies indicated that PPARγexpressed in peripheral blood monocytes of normal subjects and patients with ACS. Compared with normal subjects, patients with ACS had higher level of serum HsCRP (8.07±0.51 versus 2.99±0.15mg/L, respectively;p<0.05) and lower PPARγexpression in monocytes (1.15±0.43 versus 5.93±0.54, respectively;p<0.05). Expression of PPARγin patients with AMI was lower than that in patientswith unstable angina.(0.51±0.42 versus 3.13±0.88, respectively;p<0.01 ). Serum level of hsCRP in patients with AMI was higher than that in patients with UA(16.07±0.86 versus 5.21±0.72mg/L, respectively;p<0.01). PPARγexpression in monocyte increased and serum hsCRP decreased after treatment. The effect of atorvastatin 40mg/d on PPARγand hsCRP was more effective than that of atorvastatin 10mg/d( PPARγ: 3.38±0.12 versus 0.51±0.02 , respectively;P<0.01 ; HsCRP : 11.45±2.14 versus 1.00±2.25mg/L, respectively; p<0.01).In vitro studies, PPARγexpression in monocytes after incubation with atorvastatin for 24 hours was significantly increased(0.68±0.17 versus 0.56±0.02,respectively; p<0.01), this effect could be reversed by mevalonate.Conclusion 1.Both normal subjects and patients with ACS have expression of PPARγin monocytes.The PPARγexpression in normal subjects is higher than that people with ACS. 2.The PPARγexpression decrease with the aggravation of ACS.3.Atorvastation improve the level of PPARγexpression. The effect of atorvastatin 40mg/d on PPARγis more effective than that of atorvastatin 10mg/d.Atorvastatin influence the expression of PPARγvia inhibition of mevalonate.4.Atorvastation can significantly decrease the serum leves of HsCRP in patient with ACS, which means it has anti-inflammatory effect. Our investigations imply part of this anti-inflammatory effects may be mediated by activation of PPARγ.更多还原