恩格列净通过剂量依赖性调控自噬对心肌梗死大鼠室性心律失常的影响

Effect of Empagliflozin on ventricular arrhythmias in rats with myocardial infarction by dose-dependent regulation of autophagy

目的 探究钠-葡萄糖共转运蛋白2抑制剂恩格列净(empagliflozin,EMPA)对心肌梗死大鼠室性心律失常(ventricular arrhythmias,VAs)的影响及其可能机制。方法 采用结扎雄性非糖尿病SD大鼠左冠状动脉前降支的方法建立心机梗死(myocardialinfarction,MI)模型,将其分为MI组、low-EMPA组(10 mg/kg·d)和high-EMPA组(30 mg/kg),Sham组不行冠脉结扎术,只行开胸术。药物连续干预4周后行超声心动图、burst刺激检测VAs诱导率,HE染色观察心肌形态,western blot检测自噬相关蛋白P62、Beclin-1、LC3Ⅰ、LC3Ⅱ。结果 (1)心脏彩超:与Sham组相比,MI组大鼠左室前壁厚度(LVAWT)、室间隔厚度(IVST)、射血分数(EF)明显降低(P <0.05),左室舒张末期内径(LVEDD)、左室收缩末期内径(LVEDS)明显升高(P <0.05),左室后壁厚度差异无统计学意义(P> 0.05)。与MI组相比,low-EMPA组和high-EMPA组大鼠LVAWT、IVST、EF显著升高(P <0.05),LVEDD、LVEDS显著降低(P <0.05),LVPWT差异无统计学意义(P> 0.05)。与high-EMPA组相比,low-EMPA组LVAWT、LVPWT、EF没有统计学差异(P> 0.05),IVST明显增加(P <0.05),LVEDS、LVEDD明显降低(P <0.05)。(2)VAs发生情况:与Sham组相比,MI组大鼠VAs得分明显升高(P <0.05);与MI组大鼠相比,low-EMPA组和high-EMPA组大鼠VAs得分明显降低(P <0.05),其中high-EMPA组Vas得分降低更明显,但与low-EMPA组相比差异无统计学意义(P> 0.05);(3)Western blot:与Sham组相比,MI组P62表达增加(P <0.05),Beclin-1、LC3Ⅱ表达降低(P <0.05);与MI组相比,low-EMPA组和high-EMPA组P62表达降低(P <0.05),Beclin-1、LC3Ⅱ表达增加(P <0.05);与low-EMPA组相比,high-EMPA组P62表达降低(P <0.05),Beclin-1、LC3Ⅱ表达增加(P <0.05)。结论 EMPA可剂量依赖性改善心肌梗死大鼠VAs的诱导率,其机制可能是改善心功能及心脏结构重构、激活心肌细胞自噬。

Objective To investigate the effect of Sodium-glucose co-transporter 2 inhibitor,Empagliflozin(EMPA),on ven⁃tricular arrhythmias(VAs)in myocardial infarction(MI)rats and its possible mechanism.Methods The MI models of non-diabetic male SD rats were established by ligation of the anterior descending branch of the left coronary artery,and the rats were divided into MI group,low-EMPA group(10 mg/kg/d)and high-EMPA group(30mg/kg).The Sham group underwent thoracotomy but was not treated with coronary ligation.Drug intervention continued for 4 weeks.After 4 weeks,echocardiography was performed,the induction rate of VAs was detected by burst stimulation.Myocardial morphology was observed by HE staining,and autophagy related proteins P62,Be⁃clin-1,LC3I and LC3II were detected by western blot.Results①Ultrasonography:Compared with Sham group,LVAWT,IVST and EF in MI group were significantly decreased(P<0.05),LVEDD and LVEDS were significantly increased(P<0.05),with no statistically significant differences in LVPWT(P>0.05).Compared with the MI group,LVAWT,IVST and EF in low-EMPA group and highEMPA group were significantly increased(P<0.05),whereas LVEDD and LVEDS were significantly decreased(P<0.05),with no statistically significant differences in LVPWT(P>0.05).While LVAWT,LVPWT and EF of low-EMPA group and high-EMPA group had no statistical difference(P>0.05).The IVST of low-EMPA group was significantly higher than that of high-EMPA group(P<0.05).The LVEDS and LVEDD of low-EMPA group were significantly lower than those of high-EMPA group(P<0.05).②VAs scores:Compared with the Sham group,VAs scores in MI group were significantly higher(P<0.05);Compared with the MI group,VAs scores in low-EMPA group and high-EMPA group were significantly decreased(P<0.05),with the effect of the high-EMPA group be⁃ing more obvious,but there was no significant difference in VAs scores between the low-EMPA group and high-EMPA group(P>0.05).③Western blot:Compared with the Sham group,the expression of P62 in the MI group increased(P<0.05),while Beclin-1,LC3II expression decreased(P<0.05).Compared with the MI group,the expression of P62 in the low-EMPA and high-EMPA groups decreased(P<0.05),with Beclin-1 and LC3II expression increasing(P<0.05).Compared with the high-EMPA group,the expres⁃sion of P62 in the high-EMPA group decreased(P<0.05),with Beclin-1 and LC3II expression increasing(P<0.05).Conclusion EMPA could significantly improve the induction rate of VAs dose-dependently in rats with myocardial infarction,and its possible mechanism was to improve cardiac function and cardiac structure remodeling and activate myocardial autophagy.