利拉鲁肽对高血压大鼠心肌重构的影响

Effect of liraglutide on myocardial remodeling in hypertensive rats

目的观察利拉鲁肽对高血压大鼠心肌重构的影响,探讨白细胞介素(IL)-6/信号转导及转录激活因子3(STAT3)信号通路在其中的作用。方法40只自发性高血压Wistar大鼠随机分为高血压组、利拉鲁肽组、激活剂组、利拉鲁肽+激活剂组各10只,血压正常Wistar大鼠10只为对照组。利拉鲁肽组大鼠皮下注射利拉鲁肽0.4mg/(kg·d),激活剂组大鼠腹腔注射STAT3激活剂colivelin1mg/(kg·d),利拉鲁肽+激活剂组大鼠皮下注射利拉鲁肽0.4mg/(kg·d)+腹腔注射colivelin1mg/(kg·d),高血压组、对照组大鼠均皮下和腹腔注射生理盐水1mL/d,5组均连续注射12周。造模后测量5组大鼠收缩压、舒张压、心脏指数和左心室指数,采用ELISA法检测心肌组织IL-1β、肿瘤坏死因子-α(TNF-α)水平,采用Masson染色法检测心肌组织胶原容积分数(CVF),采用实时荧光定量PCR法检测心肌组织Ⅰ型胶原、Ⅲ型胶原mRNA相对表达量,采用Westernblot法检测心肌组织Ⅰ型胶原、Ⅲ型胶原、IL-6、IL-1β、TNF-α、p-STAT3、STAT3蛋白相对表达量并计算p-STAT3/STAT3。结果高血压组、利拉鲁肽组、激活剂组、利拉鲁肽+激活剂组收缩压[(189.55±19.06)、(153.72±13.48)、(208.51±19.33)、(171.14±15.62)mmHg]、舒张压[(158.34±13.70)、(122.18±11.77)、(173.53±16.84)、(143.70±13.57)mmHg]、心脏指数[(0.43±0.04)%、(0.36±0.03)%、(0.47±0.04)%、(0.39±0.03)%]、左心室指数[(0.36±0.04)%、(0.25±0.03)%、(0.40±0.03)%、(0.31±0.04)%]均高于对照组[(128.39±12.57)mmHg、(108.42±8.55)mmHg、(0.32±0.04)%、(0.20±0.03)%](P<0.05),高血压组、利拉鲁肽组、激活剂组、利拉鲁肽+激活剂组心肌组织IL-1β[(93.13±11.52)、(55.89±9.40)、(123.49±15.04)、(73.48±7.32)ng/L]、TNF-α[(125.29±11.57)、(88.34±9.32)、(159.46±14.90)、(103.58±12.33)ng/L]水平及CVF[(28.47±4.50)%、(9.36±1.22)%、(43.69±9.53)%、(16.74±5.67)%]均高于对照组[(35.69±6.33)ng/L、(50.67±8.44)ng/L、(2.04±0.58)%](P<0.05),高血压组、利拉鲁肽组、激活剂组、利拉鲁肽+激活剂组心肌组织Ⅰ型胶原、Ⅲ型胶原mRNA相对表达量及Ⅰ型胶原、Ⅲ型胶原、IL-6、IL-1β、TNF-α蛋白相对表达量和p-STAT3/STAT3均高于对照组(P<0.05);以上指标激活剂组均高于高血压组、利拉鲁肽组、利拉鲁肽+激活剂组(P<0.05),高血压组均高于利拉鲁肽组、利拉鲁肽+激活剂组(P<0.05),利拉鲁肽+激活剂组均高于利拉鲁肽组(P<0.05)。结论利拉鲁肽可减轻高血压大鼠心肌组织胶原沉积和炎性反应,改善心肌重构,降低血压,可能是通过抑制IL-6/STAT3信号通路发挥作用。

Objective To observe the effect of liraglutide on myocardial remodeling in hypertensive rats,and investigate the role of interleukin-6(IL-6)/signal transducer and activator of transcription 3(STAT3).Methods Forty Wistar rats with spontaneously hypertension were randomly divided into hypertension group,liraglutide group,activator group and liraglutide+activator group,with 10 rats each,and another 10 Wistar rats with normal blood pressure were as controls(control group).The rats in liraglutide group were subcutaneously injected with liraglutide 0.4 mg/(kg·d),the rats in activator group were intraperitoneally injected with STAT3 activator colivelin 1 mg/(kg·d),and the rats in liraglutide+activator group were intraperitoneally injected with liraglutide 0.4 mg/(kg·d)+colivelin 1 mg/(kg·d),and the rats in hypertension group and control group were injected with 1 mL of normal saline subcutaneously and intraperitoneally every day,totally for 12 weeks.The systolic blood pressure,diastolic blood pressure,cardiac indexes and left ventricular indexes were measured.The levels of IL-1βand tumor necrosis factor-α(TNF-α)in myocardial tissues were detected by ELISA,and the collagen volume fraction(CVF)in myocardial tissues was detected by Masson staining.Real-time fluorescence quantitative PCR was used to detect the relative expressions of typeⅠandⅢcollagen mRNAs in myocardial tissues.The relative expressions of typeⅠcollagen,typeⅢcollagen,IL-6,IL-1β,TNF-α,p-STAT3 and STAT3 proteins in myocardial tissues were detected by Western blot method.p-STAT3/STAT3 was calculated.Results The systolic blood pressures[(189.55±19.06),(153.72±13.48),(208.51±19.33),(171.14±15.62)mmHg],diastolic blood pressures[(158.34±13.70),(122.18±11.77),(173.53±16.84),(143.70±13.57)mmHg],cardiac indexes[(0.43±0.04)%,(0.36±0.03)%,(0.47±0.04)%,(0.39±0.03)%],left ventricular indexes[(0.36±0.04)%,(0.25±0.03)%,(0.40±0.03)%,(0.31±0.04)%],IL-1βlevels[(93.13±11.52),(55.89±9.40),(123.49±15.04),(73.48±7.32)ng/L],TNF-αlevels[(125.29±11.57),(88.34±9.32),(159.46±14.90),(103.58±12.33)ng/L]and CVFs[(28.47±4.50)%,(9.36±1.22)%,(43.69±9.53)%,(16.74±5.67)%]in hypertension group,liraglutide group,activator group and liraglutide+activator group were higher than those in control group[(128.39±12.57)mmHg,(108.42±8.55)mmHg,(0.32±0.04)%,(0.20±0.03)%,(35.69+6.33)ng/L,(50.67+8.44)ng/L,(2.04+0.58)%],the relative expressions of collagen typeⅠmRNA,collagen typeⅢmRNA,collagen typeⅠprotein,collagen typeⅢprotein,IL-6 protein,IL-1βprotein and TNF-αprotein as well as p-STAT3/STAT3 ratios were higher in hypertension group,liraglutide group,activator group and liraglutide+activator group than those in control group(P<0.05),and all these above indexes were higher in activator group than those in hypertension group,liraglutide group and liraglutide+activator group(P<0.05),higher in hypertension group than those in liraglutide group and liraglutide+activator group(P<0.05),and higher in liraglutide+activator group than those in liraglutide group(P<0.05).Conclusion Liraglutide can reduce collagen deposition and inflammatory response,improve myocardial remodeling,and lower blood pressure in hypertensive rats,possibly by inhibiting IL-6/STAT3 signaling pathway.