过氧化物酶体增殖物激活受体α／γ双激动剂对低密度脂蛋白受体基因敲除糖尿病小鼠动脉粥样硬化斑块稳定性的影响  

作　　者：张步春[1] 李宪凯[1] 车文良[1] 李伟明[1] 侯磊[1] 魏毅东[1] 徐亚伟[1] 

机构地区：[1]同济大学附属第十人民医院心内科,上海200072

出　　处：《中华心血管病杂志》2013年第2期143-149,共7页Chinese Journal of Cardiology

基　　金：国家自然科学基金（81200198,81000113,30800466,81270193）

摘　　要：目的探讨过氧化物酶体增殖物激活受体（PPAR）α／γ双激动剂对低密度脂蛋白受体基因敲除（LDLr-／-）糖尿病小鼠动脉粥样硬化斑块稳定性的影响。方法取4周龄雌性LDLr-／-小鼠45只，高糖高脂饮食喂养4周后采用随机数表法随机分为3组（每组15只），即对照组、2型糖尿病模型组（DM组）和PPARα／γ双激动剂替赛格列他（tesaglitazar）糖尿病治疗组（治疗组）。对照组仅给予高糖高脂饮食喂养。DM组给予高糖高脂饮食联合小剂量链脲佐菌素诱导。治疗组饲料中混合20μg/kg tesaglitazar喂养。随机分组后继续高糖高脂饮食喂养6周。药物干预6周后处死小鼠，分别于药物干预前和处死前测定小鼠体质量、血清总胆固醇（Tc）、甘油三酯（TG）和血糖（Glu）水平。免疫印迹和免疫组织化学染色检测头臂干动脉斑块炎症因子细胞间黏附分子1（ICAM-1）、血管内皮黏附分子1（VCAM-1）、单核细胞趋化蛋白-1（MCP-1）表达水平。苏木素伊红、油红0、天狼猩红染色观察头臂干动脉斑块，免疫组织化学染色检测头臂干动脉斑块平滑肌肌动蛋白（d—SMA）和巨噬细胞表面分子-3（Mac．3）表达。结果DM组小鼠血清TC、TG和Glu水平均显著高于对照组，分别为（32．34±3．26）mmol／L比（16．17±1．91）mmol／L、（3．57±0．99）mmolYL比（2．21±0．11）mmol／L和（15．21±4．67）mmoL／L比（6．89±0．83）mmol／L（P均〈0．01）。DM组小鼠头臂干动脉斑块炎症因子ICAM-1、VCAM．1和MCP．1的蛋白表达水平均显著高于对照组，分别为2．31±0．35比1．34±0．21，1．65±0．14比0．82±0．26和2．27±0．16比1．56±0．23（P均〈0．01）。DM组小鼠血管斑块面积显著大于对照组[（4．597±1．260）×103μm2比（0．0754-0．030）×103μm2]，脂质、α-SMA、Mac-3和胶原含量均显著高于对照组，分别为（47．23±2．64）％比（9．67±1．7Objective To investigate the effects of peroxisome proliferator-activated receptor (PPAR) α/γ agonist on atherosclerotic plaque stabilization in diabetic LDL receptor knockout(LDLr-/-)mice.Methods Female 4-week-old LDLr-/-mice fed with high-glucose and high-fat diet for 4 weeks were randomly divided into three groups (n =15 each): control group (only fed with high-glucose and high-fat diet),diabetic group [induced by high-glucose and high-fat diet combined with a low-dose of streptozotocin (STZ)] without tesaglitazar and with tesaglitazar (20 μg/kg oral treatment).Mter 6 weeks,the mice were sacrificed,body weight,fasting blood glucose (Glu),total cholesterol (TC),triglyceride (TG) levels were measured.The expression of ICAM-1,VCAM-1,MCP-1 in the brachiocephalic atheroselerotic lesions were determined by Western blot and immunohistochemistry,respectively.Brachiocephalic artery was prepared for morphologic study (HE,oil red O,Sirius red staining) and immunohistochemical analysis (macrophage surface molecule-3,α-smooth muscle actin),respectively.Results Serum TC [(32.34 ± 3.26) mmol/Lvs.(16.17 ±1.91) mmol/L],TG[(3.57 ±0.99) mmol/L vs.(2.21 ±0.11) mmol/L] and Glu[(15.21 ±4.67) mmol/L vs.(6.89 ± 0.83)mmol/L] levels were significantly higher in diabetic group than in the control group (all P ＜ 0.01).The expression of ICAM-1 (2.31 ± 0.35 vs.1.34 ± 0.21),VCAM-1 (1.65 ±0.14 vs.0.82 ±0.26),MCP-1 (2.27 ± 0.16 vs.1.56 ± 0.23) were significantly upregulated in diabetic group compared with control group (all P ＜ 0.01).Brachiocephalic atheroselerotic plaque area [(4.597 ±1.260) ×103 μm2 vs.(0.075 ±0.030) ×103 μm2],lipid deposition [(47.23 ±2.64)％ vs.(9.67 ±1.75)％],Mac-3 positive area [(19.15 ± 3.51)％ vs.(1.72 ± 0.16)％],α-smooth muscle actin [(5.54 ± 1.17) ％ vs.(2.13 ± 0.41) ％] and collagen content [(4.27 ± 0.74) ％ vs.(0.43 ± 0.09) ％]were all significantly larger/higher in diabetic LDLr-/-mice than in the control group (all P ＜ 0.01).While tesaglitazar treatment significantly

关 键 词：动脉粥样硬化 过氧化物酶体增殖物激活受体 糖尿病 2型 受体 LDL 小鼠 基因敲除 

分 类 号：R587.2[医药卫生—内分泌]