The Role And Mechanism Of TL1A And Its Receptor DR3,DcR3 In Acute Myocardial Ischemia Necrosis

BackgroundMyocardial ischemia and necrosis involved in inflammatory response are the most basic pathological changes of ACS.TL1A(tumor necrosis factor ligand-related molecule-1A).A newly discovered TNFSF member,plays an important role in inflammatory response and cell proliferation/death by being bound to the receptors DR3(death receptor 3)and DcR3(decoy receptor 3).The following three parts are intended to explore the relationship and mechanism of TL1A,DR3,DcR3 and acute myocardial injury and necrosis.Part 1 The Level and Clinical Significance of Soluble TL1 A,DR3 and DcR3 in Intracoronary and Peripheral BloodAimsTo investigate the possible mechanism of their correlation with the prognosis and effects of ACS by detecting intracoronal and peripheral blood TL1A,DR3,DcR3 and hs-CRP,MPO and IL-10 concentrations and their correlation,and conducting two-year follow-up.Methods1.The patients were divided into 6 groups(control group,UA group,STEMI emergency group,STEMI elective group,NSTEMI emergency group and NSTEMI elective group).2.TL1A,DR3,DcR3 and hs-CRP,MPO and IL-10 levels were detected by ELISA.3.Follow-up was performed for 2 years to record MACE events.4.TL1A,DR3,DcR3 were combined with hs-CRP,MPO,IL-10 and high-risk clinical characteristics Score and MACE events to do correlation analysis.Results1.TL1A and DR3 levels in the intracoronary and peripheral blood of the STEMI and NSTEMI of emergency and selective groups were increased,and DcR3 levels were decreased,and there were differences in the indicators of concentration between intracoronary and peripheral blood(P<0.05).Hs-CRP and MPO were increased,IL-10 was decreased,and there were no differences in the indicators of concentration between intracoronary and peripheral blood(P>0.05).2.TL1A,DR3,DcR3 were correlated with MACE event,the high risk clinical characteristic index of hs-CRP,MPO,and IL-10(P<0.05),but not with Syntax score(P>0.05).ConclusionTL1A and its receptor DR3 and DcR3 may be involved in the occurrence and development of acute coronary syndrome.Part 2 Expression of TL1A and Its Receptor DR3 and DcR3 after Myocardial Ischemic Necrosis in RatsAimsTo observe the expression of TL1A,DR3 and DcR3 after acute myocardial infarction in rats,and to investigate their roles and mechanism in the process of acute myocardial ischemic necrosis.MethodsThe acute myocardial infarction model was established.Rats were divided into 8 groups.Serum cTn1 and myoglobin were detected;hemodynamic and cardiac function indexes were determined;myocardial infarction area was detected by modified Masson staining;mRNA transcription of TL1A,DR3 and DcR3 was detected by qPCR,protein expressions of TL1A,DR3 and DcR3 were detected by immunohistochemistry and Western blot,and concentrations of IL-10,hs-CRP and MPO were detected by ELISA.Results1.Increased infarct area and degree of myocardial fibrosis after myocardial infarction(P<0.05),LVSP,±dp/dtmax,LVFS%decreased and LVEDP,LVEDS and LVEDD increased(P<0.05).2.The level of TL1A,DR3,DcR3 and hs-CRP,MPO,IL-10 and Troponin I/myoglobin were changed after myocardial infarction.(P<0.001).ConclusionsTL1A,DR3 and DcR3 may participate in the process of acute myocardial ischemic necrosis by inflammatory response.Part 3 Effects of anti-TL1A antibody on myocardial ischemic necrosis in ratsAimsTo investigate the effect and mechanism of anti-TL1A antibody on acute myocardial infarction in rats.MethodsThe rats were divided into control group,low group,medium group and high dose group and were treated with anti-TL1A antibody.The rest methods is the same as the part 2.Results1.LVSP,±dp/dtmax,LVFS%and IL-10 were increased in the medium and high dose groups.LVEDS,LVEDD,area of left ventricular infarction,degree of fibrosis,TL1A mRNA,hs-CRP,protein expression of MPO and TL1A was decreased(P<0.05).2.TL1A in the medium and high dose groups was correlated with LVSP,±dp/dtmax,LVEDP,LVSP,±dp/dtmax,MPO,hsCRP and IL-10(P<0.05).ConclusionsAnti-TL1A antibody can control the occurrence and development of myocardial ischemic necrosis by inhibiting inflammatory response.TL1A may be a potential new target for interfering with ischemic myocardium.