| Objective:This research is designed to explore the protective effects of aerobic interval training (AIT) on cardiac regeneration and heart function after myocardial infarction (MI), and discuss its possible mechanism.Methods:There were 72 male sprague-dawley rats divided into 6 groups: sendentary control group(C), aerobic interval training group(CE), Sham-operated group(S), sedentary MI group(MI), MI with training group(ME) and ME with inhibitor AG1478 group(MEA) after 1 week adaptive breeding. The left anterior descending coronary artery was ligated in order to make MI model, and the Shom-operation was established by threading only without Hgation.Rats in CE group were forced to lead 8-week treadmill running, and rats in ME and MEA groups started the training 1 week after MI operation, besides rats in MEA group were injected AG1478(10?g/kg) from caudal vein the first two days.The AIT protocol:the adaptive running (10m/min×30min) last to 1 week, the normal running started with 10m/min X 1 Omin,gradually increased to 25m/min X 7min, and decreased to 15m/min×3min, total running time is 60min every day,5 days in lweek, lasted to 8 weeks.The next day after the end of training, all the rats were anesthetized and opened chest. The heart function index LVSP, LVEDP and ądp/dtmax were tested by Carotid artery intubation. Then the hearts were fast obtained and made into histological sections. Masson stain was preformed to evaluate the collagen volume fraction (CVF). RT-qPCR was preformed to test the mRNA expression of NRG1 and its receptor ErbB2/4. Western Blot was preformed to test the protein expression of NRG1, ErbB2/4, PI3K/Akt, Bcl-2, Bax, eNOS and VEGF. Immunofluorescence method was used to observe positive expression of ?-SMA. Immunohistochemical method was used to observe positive expression of CD31.Results:(1) Expression of NRG1 and its receptors ErbB2/4 gene and protein in normal myocardium can be significantly up-regulated through aerobic interval training(AIT). There are NRG1 and its receptor ErbB2/4 gene and protein expressing in normal heart, and aerobic interval training can significantly induce the expression of NRG 1 and its receptors ErbB2/4 gene and protein in myocardium.(2) Expression of nrgl and its receptors erbb2/4 gene in the heart of myocardial infarction can be significantly up-regulated through AIT. Expression of erbb4 mRNA was significantly decreased, nrgl and erbb2 mRNA have the trend to ba decreased, but there was no significant difference. AIT significantly up-regulated the expression of nrg1and erbb2/4 mRNA, and the effect was attenuated by the inhibitor AG1478.(3) Expression of NRG1 and its receptors ErbB2/4 protein in the heart of myocardial infarction can be significantly up-regulated through AIT. Expression of NRG1 and ErbB2/4 protein was significantly decreased, AIT significantly up-regulated the expression of NRG1 and ErbB2/4 protein, and the effect was attenuated by the inhibitor AG1478.(4) The heart weight and heart weight/tibia length in rats with myocardial infarction significantly increased, collagen volume fraction (CVF) and the levels of myocardial fibrosis significantly decreased after AIT; meanwhile, LVSP and DP/ dtmax significantly increased, LVEDP significantly decreased, indicating that AIT can significantly improve the pathological remodeling of myocardial infarction, improve the heart function, and play a protective effect in heart.(5) Correlation analysis showed that NRG1 expression was significantly correlated with the level of cardiac function, indicating that the expression of NRG1 was closely related to the improvement of cardiac function.(6) AIT could significantly inhibit the cardiomyocyte apoptosis. After Myocardial infarction the caspase-3 activity significantly increased, TUNEL staining positive cells significantly increased, Bcl-2/Bax ratio significantly decreased; AIT could inhibit the activity of Caspase-3 and expression of TUNEL staining positive cells notably, and significantly increased Bcl-2/Bax ratio, but the effect was attenuated by the inhibitor AG1478.(7) AIT could significantly promote myocardial angiogenesis. After Myocardial infarction, the positive expression of heart CD31 and a-SMA increase notably, VEGF expression decreased significantly; AIT could further enhance the expression of CD31 and a-SMA, significantly improve the expression of VEGF, but the effect was attenuated by the inhibitor AG1478.(8) AIT could activate the PI3K-Akt-eNOS-VEGF signaling pathway. The phosphorylation of PI3K, Akt and eNOS was inhibited after Myocardial infarction, expression of VEGF decreased significantly; AIT could enhance the phosphorylation of PI3K, Akt and eNOS notably,significantly restore expression of VEGF, but the effect was attenuated by the inhibitor AG1478,indicating that AIT could activate the PI3K-Akt-eNOS signaling pathway and induce myocardial angiogenesisConclusion:(1) AIT could significantly increase the expression of NRG1 and its receptors ErbB2/4 gene and protein both in normal and myocardial infarction hearts.(2) AIT could significantly improve cardiac pathological remodeling and heart function, play a protective effect in heart, and the expression of NRG1 was closely related to the improvement of cardiac function; AIT could significantly inhibit the cardiomyocyte apoptosis, promote myocardial angiogenesis, but the effect was attenuated by the inhibitor AG1478;indicating that AIT may inhibit the cardiomyocyte apoptosis and promote myocardial angiogenesis through the protective role of NRG1 in the heart.(3) The activation of NRG1/ErbB2/4-PI3K-Akt-eNOS-VEGF signaling pathway may be one of the mechanisms of AIT to promote myocardial angiogenesis, inhibit cardiomyocyte apoptosis, improve myocardial remodeling and restore the heart function. |
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