2型糖尿病大鼠主动脉Wnt/β-catenin信号通路的变化及SIRT1的调节作用  

Alteration of Wnt/β-catenin signaling pathway in type2 diabetic rats' aorta and regulation of SIRT1

作　　者：尹茂山 许淑红[3] 王燕[1] 孙晓慧[1,2] 梁辰[1,2] 李杰[1] 牟艳玲[1] 

机构地区：[1]山东省医学科学院药物研究所,山东济南250062 [2]济南大学山东省医学科学院医学与生命科学学院,山东济南250062 [3]中国药科大学,江苏南京211198

出　　处：《中国药理学通报》2016年第3期337-342,共6页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 30701022);山东省优秀中青年科学家科研奖励基金计划(No BS2013SW008)

摘　　要：目的检测Wnt/β-catenin信号通路相关蛋白及沉默信息调节因子(SIRT1)在2型糖尿病大鼠主动脉中的表达变化,探究SIRT1对Wnt/β-catenin信号通路的调节作用,明确二者在糖尿病主动脉病变发生发展中的作用。方法高脂饮食联合链脲佐菌素建立2型糖尿病大鼠模型,实验将大鼠分为空白对照组、糖尿病2、4、8和12周模型组,血清检测空腹血糖(FBG),总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL-C)、低密度脂蛋白(LDL-C),空腹胰岛素(FINS),HE染色法观察主动脉病理结构变化,RT-PCR法和Western blot法检测主动脉Wnt2、β-catenin、TCF4、SIRT1和s FRP2等相关蛋白基因转录及表达变化。结果与正常组比较,2型糖尿病大鼠TC、TG、LDL-C水平明显升高,HDL-C水平明显降低,随着时间延长,糖尿病大鼠各时间点模型组与2周模型组相比较,TC、TG、LDL-C水平升高越来越明显,HDL-C水平降低更明显,差异均具有显著性(P<0.01);显微镜下糖尿病组大鼠主动脉可见不同程度局灶性内皮细胞空泡变性、甚至坏死。糖尿病组大鼠相对于正常对照组主动脉Wnt2和β-catenin的表达在2周及4周明显增加(P<0.01),4周后维持在较高水平;而TCF4、SIRT1的表达与正常对照组相比表现为持续的增加(P<0.01);s FRP2的表达在持续的降低(P<0.01)。结论 2型糖尿病大鼠主动脉病变发生发展过程中,SIRT1通过调节s FRP2的表达来调控Wnt/β-catenin信号通路的激活,参与糖尿病主动脉损伤的发生发展过程,进一步研究其在糖尿病主动脉损伤中的作用机制可能为糖尿病主动脉病找到新的治疗靶点。Aim To investigate the alteration of Wnt /β-catenin signaling and sirtuins 1in type 2 diabetic rats' aorta and clarify its role in the development of diabetes aortic disease.Methods The type 2 diabetes rat model was established by injection of streptozocin after five-week of high fat diet.The rats were randomly divided into control group, DM model group of 2weeks,4 weeks,8 weeks and 12 weeks.Fasting blood glucose(FBG),total cholesterol(TC),triglyceride(TG),high density lipoprotein-cholesterol(HDL-C),low density lipoprotein- cholesterol(LDL-C) and fasting insulin(FINS) levels were tested.HE staining was used to observe the pathological changes of aortal structures.The alteration of Wnt2, β-catenin, TCF4,SIRT1 and s FRP2 in aortawas determined by Western blot and RT-PCR.Results Compared with control group,TC,TG,LDL-C levels of type 2 diabetic rats were significantly increased,HDL-C levels were significantly reduced(P<0.01).Aortic histological analysis revealed that DM induced aortic endothelial cell vacuolar degeneration and necrosis.The expression of Wnt2 and β-catenin level increased significantly in the first 4 weeks of diabetic groups compared to control group,and that in model group of 8 weeks and 12 weeks kept in the high level and showed no significant alteration(P>0.05).But the expression of TCF4 and SIRT1 was enhanced continuously in DM compared with control group while s FRP2 decreased in the duration of DM development.Conclusions Wnt/β-catenin signaling pathway was activated in diabetic aortal injury by regulation of SIRT1 via s FRP2.Further researches on its mechanism of actionin DM aorta injury may find a new therapeutic target for the disease.

关 键 词：Wnt2 β-catenin TCF4 SIRT1 SFRP2 2型糖尿病 主动脉损伤 

分 类 号：R-332[医药卫生] R322.121