Aerobic Interval Training Activated MiR-21/PTEN/AKT/SIRT1 Pathway Inhibits NLRP3 Inflammasome Expression And Improves Myocardial Remodeling In Myocardial Infarction

Objetives: To study the effect of Aerobic interval training activated miR-21/PTEN/AKT/SIRT1 pathway inhibits NLRP3 inflammatory body expression and improves myocardial remodeling in myocardial infarctionMethods: male Sprague Dawley rats were randomly divided into four groups:Sedentary control group(C),aerobic interval exercise group(CE),Sedentary MI group(MI)and MI with AIT group(ME)(n=10).Rats in group C and CE only threaded without ligation.The MI model was established by ligation the left anterior descending coronary artery(LAD).The rats in CE and ME groups underwent treadmill exercise one week after myocardial infarction.The first week is adaptive training(15 m/min,30 min/d,total of 5days).In formal training,the initial training speed is 10 m/min and the time is 10 min.Intermittent aerobic exercise was performed at a speed of 25 m/min and 7 min,followed by a 3-min interval of 15 m/min,followed by alternate exercise for a total time of 60 min.After training for 5 days a week,rats were trained continuously for 4 wk.The rats were anesthetized in abdominal cavity,hemodynamics and electrocardiogram were used to evaluate the cardiac function.Myocardial tissue was immediately isolated and cut after death.TTC staining was used to observe myocardial infarction area,HE staining was used to observe myocardial infarction heart morphology and structure,MASSON staining was used to observe and analyze the percentage of myocardial collagen volume(CVF),DHE method was used to detect cardiac ROS,The expressions of MDA,LDH and SOD activity were detected by biochemical method.The expression of NOX4,IL-1β,IL-18,TNF-α,IL-10,NLRP3,SIRT1,AKT,p-AKT,PTEN,ASC-1 and Caspase-1 was detected in myocardium by Western Blot.The expression of miR-21,miR-155,miR-145 and miR-208 a miRNA was detected in myocardium and blood by RT-qPCR.Result:(1)Aerobic interval training significantly improves cardiac function of rats with MI.Alternative fibrosis occurred in myocardium of MI rats,with massive necrosis of myocardial cells,malignant proliferation and fusion of collagen fibers,and extended to the infarct edge area and non-infarct area.Aerobic interval training significantly reduced the level of CVF(P < 0.01),myocardial fibrosis and LVEDP and significantly increased(P <0.01),the level of LVSP and ±dp/dt max(P < 0.01).The results showed that aerobic interval training can significantly improve the pathological remodeling of myocardial infarction heart,improve cardiac function and protect cardiac function.(2)Aerobic interval training significantly inhibited oxidative stress in the heart of MI rats.The expressions of MDA,LDH,NOX4 and ROS were significantly increased in myocardium of MI rats(P < 0.01),and SOD activity was significantly decreased(P < 0.01);Aerobic interval training significantly reduced the expression of myocardial MDA,LDH,NOX4 and ROS in MI rats(P < 0.01),and significantly increased SOD activity(P < 0.01).The results showed that the heart of MI rats was under oxidative stress,and aerobic interval training could significantly inhibit the oxidative stress in the heart of MI rats.(3)Aerobic interval training significantly reduced the expression of myocardial NLRP3 inflammasome in rats with MI.The expression of NLRP3 mRNA and protein(P <0.01)and the protein expression of ASC,caspase-1,IL-1 and IL-18 were significantly increased in rats with MI(P < 0.01).Aerobic interval training significantly reduced the expression of myocardial NLRP3,ASC,Caspase-1,IL-1β and IL-18 in MI rats(P < 0.01).The results showed that MI triggered the expression of NLRP3 inflammasome,and aerobic interval training could significantly inhibit the expression of NLRP3 inflammasome in MI rats.(4)Aerobic interval training significantly reduced the expression of myocardial inflammatory factors in MI rats.The expression of myocardial inflammatory factor TNF-αwas significantly increased(P < 0.01)and the expression of anti-inflammatory factor IL-10 was significantly decreased in MI rats(P < 0.01);Aerobic interval training significantly reduced the expression of TNF-α(P < 0.01)and increased the expression of IL-10 in MI rats(P < 0.01).The results showed that MI induced the increase of inflammatory response,and aerobic interval training could significantly inhibit inflammation.(5)Aerobic interval training activated the AKT/SIRT1 signaling pathway.The expression of AKT and p-AKT protein(P < 0.01)and the expression of SIRT1 mRNA and protein were significantly decreased in MI rats(P < 0.01);Aerobic interval training significantly increased the expression of myocardial AKT,p-AKT and SIRT1 in MI rats(P< 0.01).The results showed that aerobic interval training can activate the AKT/SIRT1 signaling pathway.(6)Aerobic interval training activated the miR-21/PTEN signaling pathway.The expressions of myocardial miR-21 and PTEN was significantly increased in rats withMI(P < 0.01).Aerobic interval training could further increase the expression of miR-21 in MI rats and significantly inhibit the expression of PTEN(P < 0.01).The results showed that MI activated the miR-21/PTEN signaling pathway,and aerobic interval training could significantly activate the miR-21/PTEN signaling pathway.(7)Aerobic interval training inhibited myocardial injury specific miRNAs.The expressions of serum and myocardial miR-208 a and miR-155 were significantly increased in MI rats(P < 0.01);Aerobic interval training inhibited the expression of miR-208 a and miR-155 in the heart of rats with MI(P < 0.01).The results showed that MI induced the expression of myocardial injury specific miRNAs,and aerobic interval training significantly reduced the expression of specific miRNAs,and then improve cardiac funciton.Conclusion:(1)Aerobic interval training activated the miR-21/PTEN/AKT/SIRT1 signaling pathway in MI rats,inhibited the oxidative stress response in MI rats,reduced the percentage of collagen fiber volume,improved the rational remodeling of MI hearts,and significantly improved the cardiac function in rats with MI.(2)Aerobic interval training activated the miR-21/PTEN/AKT/SIRT1 signaling pathway in MI rats,inhibitd the expression of myocardial NLRP3 inflammasome,reduced the expression of myocardial pro-inflammatory factors,and improves cardiac function in rats with MI.(3)Aerobic interval training inhibited myocardial injury specific miRNAs in MI rats,alleviated myocardial infarction and significantly improved cardiac function in rats with MI.(4)The possible mechanism of aerobic interval training to improve myocardial infarction is to up-regulate myocardial miR-21,activate miR-21/PTEN/AKT/SIRT1 signaling pathway,and then inhibit myocardial oxidative stress and inflammatory response,thereby improve rational remodeling and significantly improve cardiac function of MI.