有氧运动通过抑制TAK1-MAPK信号通路改善压力超负荷诱导的心肌重构

Aerobic exercise ameliorates pressure overload-induced cardiac remodeling by inhibiting TAK1-MAPK signaling pathway

目的:探讨有氧运动在压力超负荷诱导的心肌重构中的作用及机制。方法:将6~8周龄雄性C57BL/6J小鼠随机分为假手术+对照(Sham+CON)组、假手术+游泳(Sham+SWIM)组、主动脉缩窄+对照(TAC+CON)组、主动脉缩窄+游泳(TAC+SWIM)组。手术后1周游泳组小鼠开始有氧运动训练。运动训练结束后,采用超声心动图检测小鼠心功能,HE染色、Masson染色和TUNEL染色分别检测心肌细胞横截面积、心肌间质纤维化和心肌细胞凋亡情况。蛋白质印迹(Western blot)法检测心房钠尿肽(ANP)、脑钠肽(BNP)、胶原蛋白(Collagen)Ⅰ和Ⅲ、Bax、Bcl-2、磷酸化转化生长因子-β-激活激酶1(p-TAK1)、磷酸化c-Jun N-末端激酶1/2(p-JNK1/2)、磷酸化细胞外信号调节激酶1/2(p-ERK1/2)和磷酸化P38(p-P38)蛋白表达水平。结果:超声心动图检测发现,与Sham+CON组相比,TAC+CON组左心室短轴缩短率(LVFS)和左心室射血分数(LVEF)明显降低(均P<0.05);有氧运动可显著提高TAC小鼠的LVFS和LVEF(均P<0.05)。HE染色、Masson染色和TUNEL染色显示,有氧运动明显降低TAC小鼠的心肌细胞横截面积、心肌间质纤维化和心肌细胞凋亡水平(均P<0.05)。Western blot分析显示,与Sham+CON组相比,TAC+CON组ANP、BNP、Bax、CollagenⅠ和CollagenⅢ蛋白表达水平升高,Bcl-2表达降低,TAK1、JNK1/2、ERK1/2和P38蛋白的磷酸化水平升高(均P<0.05)。有氧运动后,ANP、BNP、Bax、CollagenⅠ和CollagenⅢ蛋白表达水平降低,Bcl-2表达升高,TAK1、JNK1/2、ERK1/2和P38蛋白的磷酸化水平降低(均P<0.05)。结论:有氧运动可以通过抑制TAK1-MAPK通路改善TAC小鼠的心功能,改善心肌间质纤维化,减少压力超负荷诱导的心肌细胞凋亡。

Objective:To investigate the effect of aerobic exercise on pressure overload-induced myocardial remodeling and its mechanism.Methods:Male C57BL/6J mice aged 6-8 weeks were randomly allocated into sham+control(Sham+CON)group,sham+swimming(Sham+SWIM)group,TAC+control(TAC+CON)group,and TAC+swimming(TAC+SWIM)group.One week after operation,mice in the swimming groups commenced aerobic exercise training.After the aerobic training,echocardiography was employed to assess the cardiac function of the mice,while HE staining,Masson staining,and TUNEL staining were utilized to examine and analyze the cross-sectional area of myocardial cells,myocardial interstitial fibrosis,and apoptosis of myocardial cells.The protein expression levels of atrial natriuretic peptide(ANP),brain natriuretic peptide(BNP),Collagen I and III,Bax,Bcl-2,phosphorylated transforming growth factor-β-activated kinase 1(p-TAK1),phosphorylated c-Jun N-terminal kinase 1/2(p-JNK1/2),phosphorylated extracellular signal-regulated kinase 1/2(p-ERK1/2),and phosphorylated P38(p-P38)were investigated through western blot analysis.Results:Echocardiographic assessment revealed that the TAC+CON group had significantly lower left ventricular fractional shortening(LVFS)and left ventricular ejection fraction(LVEF)(all P<0.05),compared with the Sham+CON group.Aerobic exercise could significantly improve the LVFS and LVEF of TAC mice.Hematoxylin and eosin(HE)staining,Masson’s trichrome staining,and TUNEL staining demonstrated that aerobic exercise notably diminished the cross-sectional area of cardiomyocytes,myocardial interstitial fibrosis,and cardiomyocyte apoptosis in TAC mice(all P<0.05).Western blot analysis indicated that compared with the Sham+CON group,protein expression levels of ANP,BNP,Bax,Collagen I and Collagen III were increased,Bcl-2 expression was decreased,and the phosphorylation levels of TAK1,JNK1/2,ERK1/2,and P38 proteins were elevated in the TAC+CON group(all P<0.05).After aerobic exercise,protein expression levels of ANP,BNP,Bax,Collagen I and Collagen III were decreased,Bcl-2 expression was increased,and phosphorylation levels of TAK1,JNK1/2,ERK1/2,and P38 proteins were decreased(all P<0.05).Conclusion:Aerobic exercise can enhance cardiac function in TAC mice by suppressing the TAK1-MAPK signaling pathway,thus ameliorating myocardial interstitial fibrosis and mitigating pressure overload-induced cardiomyocyte apoptosis.