卡格列净通过RAS和TGF-β1/Smad途径减轻高血压诱导的心肌肥厚和纤维化

Canagliflozin attenuates hypertension induced myocardial hypertrophy and fibrosis via RAS and TGF-β1/Smad pathway

目的:研究卡格列净通过肾素血管紧张素系统(RAS)和转化生长因子-β1(TGF-β1)对自发性高血压大鼠(SHR)心室重构的影响。方法:本实验分为正常血压大鼠(WKY)组、SHR组、卡格列净低剂量[SHR-CANA(30 mg/kg)]组及卡格列净高剂量[SHR-CANA(60 mg/kg)]组,每组8例,采用灌胃法给药,1次/d,连续8周。测定血压(BP)、血糖水平,采用超声心动图评价动物心功能,采用组织形态学评价动物左心室细胞面积。实时定量聚合酶链反应和蛋白印记杂交法检测Ⅰ型胶原(Col1a)、Ⅲ型胶原(Col3a)、基质金属蛋白酶2(MMP-2)、TGF-β1、Smad4、肾素、血管紧张素Ⅱ受体1(AGTR1)和血管紧张素Ⅱ受体2(AGTR2)的表达。结果:给药8周后,SHR-CANA(30 mg/kg)组及SHR-CANA(60 mg/kg)组的心脏体重/体重比(HW/BW)、左心室重量/心脏重量比(LVW/HW)、心肌细胞面积与SHR组比较,差异有统计学意义(P<0.05)。与SHR组相比,SHR-CANA(30 mg/kg)组及SHR-CANA(60 mg/kg)组的血压、血糖和体重明显降低。与SHR组相比,SHR-CANA(30 mg/kg)组及SHR-CANA(60 mg/kg)组Col1a、Col3a、MMP2、TGF-β1、Smad4、Renin、AGTR1表达显著下调,AGTR2表达上调。结论:卡格列净可通过调节RAS和TGF-β1/Smad信号通路改善高血压诱导的心脏重构。

Objective:The objective of the present work was to study the effect of canagliflozin,a sodium – glucose co-transporter 2 inhibitor(SGLT-2i)on myocardial remodeling through renin angiotensin system(RAS)and transforming growth factor-β1(TGF-β1)in spontaneously hypertensive rats(SHR). Methods:SHRs were administered with canagliflozin once a day at a dose of 30 and 60 mg/kg body weight through an oral gavage for 8 weeks respectively. Wistar-Kyoto rats(WKY)were served as control. Blood pressure(BP)was determined by tail-cuf sphygmomanometry. Blood glucose level was measured by glucometer.The heart function of animals was evaluated by echocardiography and the degree of ventricular hypertrophy were evaluated by histomorphology. Expression collagen Ⅰ(Col1a),collagen Ⅲ(Col3a),matrix metalloproteinase 2(MMP-2),TGF-β1,Smad4,Renin,angiotensin Ⅱ type 1 receptor(AGTR1)and angiotensin Ⅱ type 2 receptor(AGTR2)was detected by real-time quantitative polymerase chain reaction and western blotting.Results:After 8 weeks of treatment,a significant difference was observed in the heart weight/body weight(HW/BW)ratio,left ventricle weight/heart weight(LVW/HW)ratio and cardiomyocyte area between canagliflozin treatment group and SHR. A significant decrease in BP,blood glucose and body weight of canagliflozin treatment group compared to SHRs was observed. The expression of col1a,col3a,MMP2,TGF-β1,Smad4,renin,AGTR1 was downregulated significantly in canagliflozin treatment group compared to SHRs,while expression of AGTR2 was upregulated.Conclusion:From the results,canagliflozin was found to ameliorate pressure overload-induced cardiac remodeling by regulating the RAS and TGF-β1/Smad signaling pathway.