Peroxisome proliferator-activated receptor α/γ agonist tesaglitazar stabilizes atherosclerotic plaque in diabetic low density lipoprotein receptor knockout mice
10.3760/cma.j.issn.0253-3758.2013.02.013
- VernacularTitle: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
- Author:
Bu-Chun ZHANG
1
;
Xian-Kai LI
;
Wen-Liang CHE
;
Wei-Ming LI
;
Lei HOU
;
Yi-Dong WEI
;
Ya-Wei XU
Author Information
1. 同济大学附属第十人民医院心内科
- Keywords:
Atherosclerosis;
Peroxisome proliferator-activated receptors;
Diabetes mellitus,type 2;
Receptors,LDL;
Mice,knockout
- From:
Chinese Journal of Cardiology
2013;41(2):143-149
- CountryChina
- Language:Chinese
-
Abstract:
Objective 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 reduced serum TC [(30.47 ± 3.18) mmol/L],TG [(3.14 ± 0.71)mmol/L] and Glu [(7.92 ± 1.28) mmol/L] levels (all P ＜ 0.01).Similarly,the expression of ICAM-1 [(1.84 ± 0.22)],VCAM-1 [(1.27 ± 0.11)],MCP-1 [(1.83 ± 0.24)],brachiocephalic atheroselerotic lesion area [(1.283 ± 0.410) × 103 μm2],lipid deposition [(23.52 ± 1.39) ％] were also significantly reduced by tesaglitazar (all P ＜ 0.05).Moreover,tesaglitazar increased o-smooth muscle actin [(9.46 ±1.47) ％] and collagen content [(6.32 ± 1.15) ％] in diabetic LDLr-/-mice (all P ＜ 0.05).In addition,lipid deposition and Mac-3 positive areas [(10.67 ± 0.88)％ vs.(15.83 ± 1.01)％] in the aortic root were also reduced in tesaglitazar treated diabetic LDLr-/-mice (P ＜ 0.01).Conclusions Tesaglitazar has antiinflammatory effects in the diabetic LDLr-/-mice.Tesaglitazar could reduce lipid deposition,increase collagen and α-SMA content in the brachiocephalic atheroselerotic lesions,thus,stabilize atherosclerotic plaque in this model.
