LCZ696 Reduces Myocardial Infarction Injury By Inhibiting NLRP3 Regulated Pyroptosis Through The TAK1/JNK Pathway

Objective: Myocardial infarction is often secondary to coronary artery disease,causing serious ischemic damage to myocardial cells in the blood supply area of the infarct-related artery and secondary damage after reperfusion.Induction of ventricular remodeling is the main cause of heart failure.the reason.A number of studies have shown that cell pyrolysis is involved in the pathological progress of ventricular remodeling after myocardial infarction.Inflammation is a key link in cell pyrolysis involved in ventricular remodeling.The NLRP3 inflammasome produced by immune activation mediates cardiomyocyte pyrolysis and induces myocardial cell pyrolysis.Cell fibrosis promotes heart remodeling.Therefore,targeted therapy to inhibit myocardial pyrolysis is the key to preventing and improving ventricular remodeling after myocardial infarction.TGF ? plays an important role in the process of ventricular remodeling and regulates cardiomyocytes by activating TGF ? activated kinase 1(TAK1)and its downstream JNK.TAK1 participates in cardiomyocyte differentiation and heart growth and development,which is very important for heart disease.TAK1 overexpression transgenic mice showed cardiac hypertrophy,interstitial fibrosis,embryonic gene expression,severe myocardial dysfunction and early death.Studies have shown that TAK1 controls cell activity and inflammation by activating downstream effectors such as NF-? B and mitogen activated protein kinase(MAPK).TAK1-JNK pathway is a key regulator of NLRP3 inflammasome activation,and whether it is involved in myocardial infarction injury remains to be confirmed.LCZ 696 is a new type of neuroendocrine inhibitor that can selectively inhibit angiotensin II receptor and enkephalinase,and can reduce the risk of long-term cardiovascular events in patients with chronic heart failure.In a clinical trial,LCZ696 improved cardiac function by inhibiting transforming growth factor-?,thus providing a new treatment option for chronic heart failure beyond RAAS blockade.However,whether it can also improve cardiac dysfunction in the short term remains to be clarified.This study aims to investigate the effects of LCZ696 on the acute phase of experimental myocardial infarction(MI)rats,and observe the effects of LCZ696 on myocardial cell inflammatory injury and early ventricular remodeling in rats after myocardial infarction.The objective is to explore the regulatory mechanism of cell pyroptosis in myocardial injury,and to clarify the role of LCZ696 in reducing the long-term mortality of myocardial infarction and the regulatory mechanism,providing a theoretical basis for the prevention and treatment of clinical myocardial infarction and post-infarction heart failure.Methods: Forty-five SPF SD rats,male,260?300 g,were used to establish a rat myocardial infarction model by coronary artery ligation.The rats were divided into 3groups by random number table: sham operation group(Sham group),Myocardial infarction model group(MI group),myocardial infarction + LCZ696 Z group(LCZ696group).After the model was established,the LCZ696 group was given LCZ696(68 mg/kg)solution by gavage every day,and the Sham group and MI group were given the same amount of normal saline for 7 days.M-mode ultrasound collected left ventricular end diastolic diameter(LVDd),left ventricular end systolic diameter(LVDs),left ventricular ejection fraction(LVEF),left ventricular short axis shortening rate(LVFS)to evaluate the structure and function of the heart of rats in each group TTC staining to observe the area of myocardial infarction in each group of rats,HE staining to observe the pathological damage of myocardial tissue in each group,Masson staining to evaluate the degree of myocardial tissue fibrosis in each group of rats,and ELISA to detect the inflammatory factor IL-in peripheral serum 6 and TNF-? expression to evaluate the inflammatory response of each group of rats,immunofluorescence detection of ROS expression in myocardial tissue to evaluate the oxidative stress response of each group of rats.Results: Compared with the MI group,the expression of TAK1 and p-JNK in the LCZ696 group was significantly reduced(P<0.05).And it changed in a dependent manner with the lengthening of the defect time(P<0.05).Overexpression of TAK1,LCZ696 inhibited the regulation of NLRP3,GSDMD,GSDMD-NT,pro-caspase-1,pro-caspase-1p10,pro-IL-1?,and pro-IL-18 in MI rats(P<0.05).Conclusion: 1.Short-term use of LCZ696 can improve early ventricular remodeling after acute myocardial infarction;2.LCZ696 can reduce myocardial injury after myocardial infarction by inhibiting inflammation;3.LCZ696 can inhibit the expression of NLRP3 inflammasome after myocardial infarction;4.LCZ696 can inhibit NLRP3 inflammasomemediated pyroptosis and reduces myocardial cell damage;5.LCZ696 mediates the downregulation of NLRP3 through the TAK1/JNK pathway to inhibit pyroptosis and reduces myocardial injury after myocardial infarction.