马来酸罗格列酮增强过氧化物酶体增殖剂活化受体γ1基因转染抗ApoE-/-小鼠动脉粥样硬化的作用  

Rosiglitazone enhances the anti-atherosclerotic effects of peroxisome proliferator-activated receptor γ1 gene transfer in Apolipoprotein-knock out mice

作　　者：胡琴[1] 张运[1] 张宪军[2] 张澄[1] 贺红[1] 朱清[1] 蒋桂花[1] 井玛[1] 姜虹[1] 刘春喜[1] 冯进波[1] 

机构地区：[1]教育部和卫生部心血管重构和功能研究重点实验室 山东大学齐鲁医院心内科,济南250012 [2]教育部和卫生部心血管重构和功能研究重点实验室 山东大学齐鲁医院皮肤科,济南250012

出　　处：《中华心血管病杂志》2007年第11期1050-1056,共7页Chinese Journal of Cardiology

摘　　要：目的探讨过氧化物酶体增殖剂活化受体(PPAR)γ活化剂马来酸罗格列酮能否增强腺病毒介导的 mPPARγ1基因转染抗 ApoE-/-小鼠动脉粥样硬化的作用。方法将20周龄ApoE-/-小鼠高脂饲养20周后随机分成4组(每组 n=10),即 AdPPARγ1组、AdPPARγ1+RO 组(病毒干预前1周予罗格列酮4 mg·kg^(-1)·d^(-1)灌胃)、AdGFP 组和 PBS 组。转染2周后比较各组小鼠主动脉根部斑块面积均值。Movat 5色套染法和油红 O 染色分析主动脉根部斑块成分变化。检测斑块内 PPARγ、血管平滑肌细胞(SM-actin)、巨噬细胞(MOMA-2)、MMP-9/TIMP-1、CD40/CD40L 和组织因子(TF)等抗原的免疫活性。结果 PBS 组与 AdGFP 组比较,各项指标差异均无统计学意义。与AdGFP 组比较,AdPPARγ1组和 AdPPARγ1+RO 组 ApoE-/-小鼠主动脉根部斑块面积和脂质含量减少(P<0.05)[AdGFP 组、AdPPARγ1组和 AdPPARγ1+RO 组病变面积均值分别为(0.98±0.17)、(0.86±0.12)、(0.79±0.15)mm^2,油红 O 染色阳性面积分别为(270±49)×10~3、(150±35)×10~3、(80±21)×10~3μm^2]。Movat 染色法显示 PBS 组和 AdGFP 组小鼠主动脉根部斑块成分差异不显著,而 AdPPARγ1组和 AdPPARγ1+RO 组纤维帽较厚、弹性纤维、胶原和蛋白聚糖含量增加。与 AdGFP组比较,AdPPARγ1组和 AdPPARγ+RO 组主动脉根部斑块 PPARγ、SM-actin、TIMP-1抗原免疫活性增强,而 MOMA-2、MMP-9、CD40/CD40L 和 TF 抗原免疫活性减弱,其中 AdPPARγ1+RO 组作用最显著。结论腺病毒介导的 mPPARγ1基因转染遏制 ApoE-/-小鼠动脉粥样硬化进程,促进动脉粥样硬化斑块向稳定表型转换,PPARγ活化剂马来酸罗格列酮增强上述作用。Objective To explore if PPARγ agonist rosiglitazone could enhance the anti-atherosclerotic effects of mouse peroxisome proliferator-activated receptor γ1 （ PPARγ1） gene transfer in apolipoprotein-knock out mice. Methods Adult ApoE-knock out mice were fed a Western-diet for 20-weeks and then injected with PBS, Ad. PPARγ1 （5×10^8pfu） or Ad. GFP（5×10^8pfu） via jugular vein. Another group of mice were intervened with rosiglitazone （dissolved in 0. 5% cellulose acetate, 4 mg·kg^-1·d^-1 , per gavage） 1 week before Ad. PPARγ1 injection （n = 10, each group）. Two weeks later, the lipid core and plaque composition were characterized with oil red O staining and Movat method respectively. The expression of PPARγ,SM-actin, MOMA-2 ,MMP-9/TIMP-1, CD40/CD40L and TF antigens in aortic roots and plaques among four groups were compared semi-quantitatively using immunohistochemical technology. Results All parameters were similar between AdGFP and PBS groups （ P 〉 0. 05 ）. The area of plaque were significantly decreased and oil red O staining area significantly increased in AdPPARγ1 [ （0. 86 ±0. 12） mm^2, （ 150 ± 35）×10^3 μm^2] and AdPPARγ1 ＋ RO [（0.79 ±0.15） mm^2, （270 ±49）×10^3μm^2] treated mice compared with AdGFP group [ （ 0. 98 ± 0. 17 ） mm^2, （ 80 ± 21 ）×10^3 μm^2 ] all P 〈 0. 05. Elastic fiber, collagen and proteoglycan in plaques were also significantly increased in AdPPARγ1 and AdPPARγ1 ＋ RO groups. Upregulation of PPARγ, SM-actin ,TIMP-1 antigen activity and downregulation of MOMA-2, MMP-9, CD40/CD40L and TF antigen activity in AdPPARγ1 and most significantly in AdPPARγ1 ＋ RO group were observed （ P 〈 0. 05）. Conclusion Anti-atherosclerotic effects of PPARγ1 gene transfer in ApoE-knock out mice could be enhanced by PPARγ agonist rosiglitazone.

关 键 词：动脉硬化 罗格列酮 过氧化物酶体增殖剂活化受体γ 

分 类 号：R543[医药卫生—心血管疾病]