The Role And Mechanism Of Tyrosine Kinase Src In β-adrenergic Receptor-induced Cardiac Remodeling

Objective: Heart failure is the end stage of many heart diseases,with progressive development and poor prognosis.It has become a serious public health problem worldwide,and its severity is mainly reflected in its high morbidity,high mortality,and the need for treatment High costs.And heart remodeling is a necessary pathological process of heart failure.Cardiac remodeling refers to changes in cardiac mass,volume,and function to adapt to changes in myocardial damage or load,and is the pathological basis of many cardiovascular diseases.The β-adrenergic receptor(β-AR)caused by cross-stimulation Excessive activation is the main pathogenesis of heart remodeling.Under sympathetic stress conditions,excessive activation of β-AR will cause pathological effects such as apoptosis and hypertrophy of cardiac myocytes,causing heart damage;and continuous activation of β-AR will cause rational reconstruction of heart disease.However,the mechanism of β-AR signal transduction pathway and its agonists causing pathological effects is still unclear.The Src kinase we are focusing on is a key tyrosine kinase downstream of β-AR,but at present,the relationship between Src and β-AR mediated cardiac remodeling is unclear.Therefore,this study aims to clarify whether tyrosine kinase Src mediates β-AR-induced cardiac remodeling and whether it can be used as a drug target for the treatment of cardiac remodeling,and provide a basis for accurate treatment of cardiac remodeling.Methods: Wild-type C57 male rats were selected to construct a cardiac remodeling model at about 12 weeks,and randomly divided into three groups: CON group(control group),ISO group(model group),and PP1+ISO group(drug intervention group),ISO group(Model group)Subcutaneous injection of β-AR agonist isoprenaline(isoprenaline)at a dose of 10 mg/kg/day for 14 consecutive days;PP1+ISO group(drug intervention group)was injected with Src at the same time as intraperitoneal injection The dosage of PP1 is 1.5 mg/kg/day at 14-day intervals;the CON group(control group)is injected with the same amount of solvent as a control.After 14 days,the structure and function of the heart of the mouse were detected by echocardiography;the cross-sectional area of cardiac myocytes and heart inflammation were detected by H&E staining;the fibrosis of the heart was detected by Sirius scarlet staining;the weight of the mouse,the length of the tibia and the weight of the heart of the mouse were recorded,calculate and count heart-body ratio and heart-tibia ratio by this method;detect the expression of ANP and BNP mRNA levels of cardiac hypertrophy markers by RT-PCR,and detect Col-Ⅰ and Col-Ⅲ mRNA of cardiac fibrosis markers Level of expression and expression of IL-1β and IL-6 mRNA levels related to cardiac inflammation;detection of cardiac fibroblast proliferation by CCK-8;expression of fibroblast proliferation marker PCNA by Western Blot;intervention in Src,The expression of p-ERK1/2,T-ERK,p-p38,T-p38,T-Src and GAPDH were detected by Western Blot.Results: The results of animal experiments show that the model of cardiac remodeling in mice is successfully constructed;inhibition of Src can reduce β-AR-induced cardiac hypertrophy;inhibition of Src can reduce β-AR-induced cardiac fibrosis;inhibition of Src can reduce β-AR-induced cardiac hypertrophy Heart inflammation.The results of cell experiments indicate that the molecular mechanism of Src-mediated cardiac remodeling is achieved by mediating ERK1/2 and p38 signaling pathways.Src inhibitor PP1 can effectively inhibit ISO-induced phosphorylation of ERK1/2 and p38,while overexpression of Src can promote ISO-induced phosphorylation of ERK1/2 and p38.Conclusion: Tyrosine kinase Src can mediate cardiac remodeling induced by β-AR;the molecular mechanism of Src-mediated cardiac remodeling is achieved by mediating β-AR downstream ERK1/2 and p38 MAPK.