| Myocardial Infarction(MI)is a cardiovascular disease with high mortality rate.In China,over one million people die of acute Myocardial Infarction(AMI)or heart failure each year.The inflammatory microenvironment after myocardial infarction plays an important role in the regulation of myocardial repair.Therefore,it is important to modulate the inflammatory microenvironment during the repair process after MI,so that progressive cardiac dysfunction,pathological remodeling and the incidence of heart failure can be reduced.The mechanism could provide new targets for better treatment of MI and provide new strategies to improve quality of life for the patients.Dendritic cells(DCs)are important regulators of inflammatory microenvironment after myocardial infarction.They are important for the tissue repair by promoting moderate inflammatory responses and removing necrotic cardiomyocytes.However,the mechanism for this repair is extremely complicated.Once the excessive inflammatory reaction is triggered,it will lead to matrix degradation and apoptosis in the heart,and the normal repairing process will be postponed.It has been reported that the number of DCs in the infarct areas and infarct margin of the heart increased and DCs have an important effect on the regulation of the inflammatory microenvironment after myocardial infarction.The DCs is the basis for mediating tissue repair by regulating inflammatory microenvironment.DCs can be divided into immature dendritic cells(im DCs)and mature dendritic cells(m DCs)according to their maturity.Immature DCs are capable of uptaking and processing antigens,and have greater motility.Mature DCs have greater antigen presenting abilities and express high level of co-stimulatory molecules,and T cell chemokine receptors,they could attract and activate T cells,and promote their proliferation and differentiation into different types T cells.The mature DCs secrete more inflammatory cytokines and chemokines,forming immune responsive and regulatory the network,thus,regulating the inflammatory microenvironment and improve the process of myocardial repair after the repair.The functions of JAKs and STATs are well known for their growth and cytokines.JAK / STAT signaling pathway can regulate the repair of tissue damage after myocardial infarction.In recent years,studies have shown that JAK2 and STAT5 can regulate DCs differentiation and maturation.However,the regulation of JAK2 / STAT5 signaling pathway on the maturation of DCs after myocardial infarction has not been reported.Our previous study found that TSA can promote the repair of tissue in the heart of rats after MI and increase the number of DCs in the infarct area.Therefore,we can see that TSA has a protective effect on the myocardium after MI and can increase the number of DCs infiltrated into the infarct area.However,the mechanisms by which TSA regulate the maturation of DCs and protect the myocardium after MI has not yet been fully clarified.We speculate that TSA may promote the repair of myocardial infarction by modulating DCs maturation and by improving the inflammatory response after MI.Objectives: The aim of this study was to investigate the role of TSA in regulating the maturation of DCs and improving the inflammatory response after myocardial infarction,thus promoting the repair of myocardial tissue.Methods: In this study,male Wistar rats were used as subjects for the research.The rat model of myocardial infarction was established by the left anterior descending coronary artery ligation.TSA or saline was administered for 5 days before operation,AG490 was administered for 3 days before operation.And the rats were sacrificed at 1 day,3d,7d,14 d and 28 days after operation.To observe the protective effects of TSA on post infarction myocardium,TTC staining was used to detect the area of myocardial infarction,and serum myocardial enzyme kits were used measure serum myocardial enzymatic activities.CD103,MHC II,CD80 and CD86 were detected by flow cytometry to monitor the timely changes of the number of mature DCs in the infarcted myocardium.To study the effects of TSA and JAK2 inhibitors on JAK2 / STAT5 signaling pathway which plays an important role in regulating DCs maturation,the expression of P-JAK2 and P-STAT5 proteins was detected by Western-blot.The effects of TSA on serum IL-1,TNF-?,IFN-?,IL-10 and TGF-? in rats with myocardial infarction were detected by ELISA.Results:(1)Compared with the sham group,myocardial infarct size in the model groupwere increased after myocardial infarction(P <0.05),the activity of CK,AST and LDH in the model group were increased(P <0.05).Compared with the model group,the infarct sizes in the TSA group were greatly reduced(P <0.05),the activity of CK,AST and LDH in TSA group decreased(P <0.05).Indicating that TSA has a protective effect on the infarcted myocardium.(2)Compared with the sham group,the number of mature DCs in model group were higher(P <0.05)and peaked at day 7(P <0.05).Compared with the model group,the number of mature DCs in TSA group were higher(P <0.05)and peaked at day 7(P <0.05).Indicating that TSA can increase the number of mature DCs in infarcted myocardium.(3)Compared with the sham group,P-JAK2 and P-STAT5 increased in the model group after myocardial infarction(P < 0.05).Compared with the model group,P-JAK2 and P-STAT5 increased in the TSA group after myocardial infarction(P < 0.05),and the trend was consistent with the number of m DCs.Compared with TSA group,Model-TSA+AG490 inhibit TSA induced P-JAK2,P-STAT5 expression(P<0.05),reduced m DCs(P<0.05).Indicating that TSA increases the number of mature DCs in myocardium through JAK2 signaling pathway.(4)Compared with sham group,the levels of IL-1,TNF-?,IFN-?,IL-10 and TGF-? in the serum of the model group were up-regulated(P<0.05).Compared with the model group,the levels of IL-1,TNF-?,IFN-? and TGF-? in the serum of the TSA group were up-regulated(P<0.05),the levels of IL-10 in the serum of the TSA group were down-regulated(P<0.05).Compared with TSA group,the levels of IL-1,TNF-?,IFN-? and TGF-? in the serum of the Model-TSA+AG490 group were down-regulated(P<0.05),the levels of IL-10 in the serum of the TSA group were up-regulated(P<0.05).Indicating that TSA regulates cytokine levels through JAK2 signaling pathway.Conclusions:(1)TSA to reduce myocardial infarct size,reduce the expression of myocardial enzymes,play a role in myocardial protection;(2)TSA increased the number of mature DCs in myocardium and changed the level of cytokines through JAK2/STAT5 signaling pathway. |
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