阿格列汀对2型糖尿病模型大鼠心肌纤维化的保护作用及其机制

Protective effect and mechanism of alogliptin on myocardial fibrosis in type 2 diabetic rats

目的观察阿格列汀(Alog)对2型糖尿病(DM2)模型大鼠心肌纤维化的保护作用,并探讨其可能的作用机制。方法采用高糖高脂联合链佐星诱导制备DM2大鼠模型。造模成功后,随机分为DM2组、Alog 5 mg·kg^-1组和DM2+Alog治疗组,同时设正常大鼠对照组,每组10只。HE染色观察大鼠心肌组织形态及病理变化;Masson染色观察大鼠心肌组织胶原纤维累积;免疫组化法检测大鼠心肌组织中胶原Ⅰ型和胶原Ⅲ型含量的变化;Western印迹法分析大鼠心肌组织中胶原Ⅰ型、胶原Ⅲ型、转化生长因子β1(TGF-β1)、TGF-β受体Ⅱ(TβRⅡ)、TGF活化激酶1(TAK1)、P38丝裂原活化蛋白激酶(P38-MAPK)和磷酸化c-Jun氨基端激酶(p-JNK)的蛋白表达。结果与正常对照组相比,DM2组大鼠心肌组织损伤明显,胶原纤维大量沉积,胶原Ⅰ型与胶原Ⅲ型表达明显增多(P<0.05);心肌组织中胶原Ⅰ型、胶原Ⅲ型、TGF-β1、TβRⅡ、TAK1、P38-MAPK和p-JNK的蛋白表达增加(P<0.05)。与DM2组相比,DM2+Alog组大鼠心肌组织损伤明显改善,胶原沉积明显减少(P<0.05);心肌组织中胶原Ⅰ型、胶原Ⅲ型、TGF-β1、TβRⅡ、TAK1、P38-MAPK和p-JNK的蛋白表达均下调(P<0.05)。结论Alog对DM2模型大鼠心肌纤维化发挥保护作用,其机制与抑制TGF-β1/P38-MAPK信号通路有关。

OBJECTIVE To observe the protective effect of alogliptin(Alog)on myocardial fibrosis in type 2 diabetes mellitus(DM2)rats and to explore the possible mechanism.METHODS A model of DM2 rats was induced by high glucose and high fat and streptozocin(STZ).After successful modeling,rats were randomly divided into the DM2 group,the Alog drug group and the DM2+Alog treatment group.Normal rats served as the control group,with 10 rats in each group.Myocardial tissue of rats was treated with hematoxylin-eosin(HE)staining for morphological and pathological changes,and with Masson staining to observe the accumulation of collagen in rat hearts.Changes in the expressions of collagen Ⅰ and collagen Ⅲ were detected via immunofluorescence.The expression levels of collagenⅠ,collagen Ⅲ,transforming growth factor-β1(TGF-β1),transforming growth factor-β receptor Ⅱ(TβRⅡ),transforming growth factor activated kinase 1(TAK1),P38 mitogen-activated protein kinase(P38-MAPK)and phos?phorylation of c-jun N-terminal kinase(p-JNK)were detected by Western blotting.RESULTS Compared to normal control group,myocardial tissue in DM2 groups was damaged obviously,collagen fibrils accu?mulated generously,and the expressions of collagen Ⅰ and collagen Ⅲ increased significantly in the myocardial tissue of rats(P<0.05).Protein expression levels of collagen Ⅰ,collagen Ⅲ,TGF-β1,TβRⅡ,TAK1,P38-MAPK and p-JNK were increased(P<0.05).Compared to DM2 group,the injury of myocar?dial tissue in DM2+Alog groups improved significantly,and collagen fibrils reduced significantly in the myocardial tissue of rats(P<0.05).Protein expression levels of collagen Ⅰ,collagen Ⅲ,TGF-β1,TβRⅡ,TAK1,P38-MAPK and p-JNK were all down-regulated(P<0.05).CONCLUSION Alog can protect against myocardial fibrosis in diabetic rats,and the mechanism is related to the inhibition of TGF-β1/P38-MAPK signaling pathway.