橙皮素通过调控SIRT1/PGC-1α信号通路保护急性心肌梗死大鼠

Hesperetin protectes against acute myocardial infarction in rats by regulating SIRT1/PGC-1αsignaling pathway

目的:探究橙皮素是否通过调控沉默信息调节因子1(SIRT1)/过氧化物酶体增殖物激活受体γ辅激活因子1α(PGC-1α)通路调节急性心肌梗死(AMI)大鼠的氧化应激反应。方法:将SD雄性大鼠随机分成:假手术组、模型组、橙皮素(30 mg/kg)组和橙皮素(30 mg/kg)+抑制剂(SIRT1抑制剂)组,每组12只。除假手术组外,其余各组采用冠状动脉左前降支(LAD)结扎术构建AMI大鼠模型。小型动物超声系统检测大鼠心脏功能;ELISA法检测大鼠血清中炎症因子白细胞介素6(IL-6)和肿瘤坏死因子(TNF-α)水平;试剂盒检测大鼠血清中氧化应激指标总超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)和丙二醛(MDA)水平;HE染色察心肌组织病理变化;TU-NEL法检测心肌组织细胞凋亡;Western blot法检测心肌组织中SIRT1/PGC-1α通路相关蛋白表达水平。结果:假手术组大鼠心肌细胞排列规则、清晰,未见明显变性;模型组大鼠部分心肌纤维排列明显紊乱,大量炎症细胞浸润;橙皮素组大鼠与模型组相比,心肌纤维排列较规则,炎症细胞浸润较轻,整体形态较为清晰;橙皮素+抑制剂组病变程度明显重于橙皮素组。与假手术组相比,模型组大鼠左心室短轴缩短率(LVFS)、左心室射血分数(LVEF)、SOD和GSH-Px及SIRT1和PGC-1α蛋白水平显著降低(P<0.05),左心室收缩末期内径(LVESD)、左心室舒张末期内径(LVEDD)、MDA、IL-6、TNF-α及心肌细胞凋亡率显著升高(P<0.05);与模型组相比,橙皮素组大鼠LVFS、LVEF和SOD和GSH-Px及SIRT1和PGC-1α蛋白水平显著升高(P<0.05),LVESD、LVEDD、MDA、IL-6、TNF-α及心肌细胞凋亡率显著降低(P<0.05);与橙皮素组相比,橙皮素+抑制剂组大鼠LVFS、LVEF、SOD和GSH-Px及SIRT1和PGC-1α蛋白水平显著降低(P<0.05),LVESD、LVEDD、MDA、IL-6、TNF-α及心肌细胞凋亡率显著升高(P<0.05)。结论:橙皮素可通过激活SIRT1/PGC-1α信号通路,抑制AMI大鼠氧化应激反应,从而发挥心脏保护作用。

AIM:To explore whether hesperetin regulates oxidative stress in rats with acute myocardial infarc-tion(AMI)through silent information regulator 1(SIRT1)/peroxisome proliferator-activated receptorγcoactivator-1α(PGC-1α)signaling pathway.METHODS:Male SD rats were randomly divided into sham operation group,model group,hesperetin(30 mg/kg)group and hesperetin(30 mg/kg)+inhibitor(SIRT1 inhibitor)group,with 12 rats in each group.Exceptsham operation group,the ligation of left anterior descending coronary artery(LAD)was used to establish the AMI rat model.Heart function in rats was measured by small-animal ultrasound system.The serum levels of interleu-kin-6(IL-6)and tumor necrosis factor-α(TNF-α)were measured by ELISA.The serum levels of total superoxide dis-mutase(SOD),glutathione peroxidase(GSH-Px)and malondialdehyde(MDA)were detected.The pathological changes and apoptosis of myocardial tissue were evaluated by HE staining and TUNEL method,respectively.The protein levels of SIRT1/PGC-1αsignaling pathway-related molecules were determined by Western blot.RESULTS:In sham operation group,the arrangement of myocardial cells was regular and clear,without obvious degeneration.In model group,the ar-rangement of some myocardial fibers was obviously disordered,and a large number of inflammatory cells was infiltrated.Compared with model group,the arrangement of myocardial fibers in hesperetin group was regular,the infiltration of in-flammatory cells was light,and the overall shape was clear.The pathological changes in hesperetin+inhibitor group were more severe than those in hesperetin group.Compared with sham operation group,left ventricular fractional shortening(LVFS),left ventricular efection fraction(LVEF),SOD,GSH-Px,SIRT1 and PGC-1αlevels in model group were signifi-cantly decreased(P<0.05),while left ventricular end-systolic diameter(LVESD),left ventricular end-diastolic diameter(LVEDD),MDA,IL-6,TNF-αand apoptotic rate of cardiomyocytes were significantly increased(P<0.05).Compared with model group,LVFS,LVEF,SOD,GSH-Px,SIRT1 and PGC-1αlevels in hesperetin group were significantly in-creased(P<0.05),while LVESD,LVEDD,MDA,IL-6,TNF-αand apoptotic rate of cardiomyocytes were significantly decreased(P<0.05).Compared with hesperetin group,LVFS,LVEF,SOD,GSH-Px,SIRT1 and PGC-1αlevels in hes-peretin+inhibitor group were significantly decreased(P<0.05),while LVESD,LVEDD,MDA,IL-6,TNF-αand apop-totic rate of cardiomyocytes were significantly increased(P<0.05).CONCLUSION:Hesperetin inhibits the oxidative stress response of AMI rats by activating SIRT1/PGC-1αsignaling pathway,thus exerting the cardioprotective effect.