Mechanisms Involved In Osteopontin-induced Atrial Fibrosis And Clinical Predictive Value Of Osteopontin

Background: Atrial fibrillation(AF)is the most common arrhythmia,and its most important histological feature is atrial fibrosis.Atrial fibrosis can not only slow down wave propagation in the atria,but hyperproliferative atrial fibroblasts can also be coupled with atrial myocytes,causing abnormal conduction in the atria.A large number of clinical studies have shown that atrial fibrosis can reduce the success rate of drugs and catheter ablation for the treatment of AF.Therefore,investigating the causes and mechanisms of atrial fibrosis is essential for the prevention and treatment of AF.Aims: To screen the key gene of AF development by bioinformatics,and investigate the role and mechanisms of this gene in the process of AF and atrial fibrosis by in vivo and in vitro experiments.Methods: R software,Origin software,Cytoscape software were used to screen the gene closely related to the occurrence of AF.HE staining,Masson staining,immunohistochemical staining and immunoblotting were used to verify the results of bioinformatics analysis.The effects of osteopontin on atrial fibrosis and the underlying mechanisms were investigated by immunofluorescence,immunoblotting,quantitative real-time PCR,cell proliferation experiments,and transmission electron microscopy.Circulating osteopontin was assessed by ELISA.Left atrial voltage in patients with AF was mapped using Penta Ray mapping catheter and Carto 3three-dimensional mapping system.Results: Bioinformatics analysis suggested that osteopontin was closely related to AF.Immunohistochemistry and immunoblotting confirmed that the expression of osteopontin in left atrial appendage of AF patients was significantly increased.Osteopontin significantly promoted proliferation and expression of fibrosis-related proteins(Collagen ? and Fibronectin)in human atrial fibroblasts.Inhibition of Akt/GSK-3?/?-catenin reversed the fibrotic phenotype of human atrial fibroblasts.Autophagy in atrial fibroblasts regulated the expression of fibrosis-related proteins(Collagen ? and Fibronectin).Circulating osteopontin in patients with AF was significantly higher than that in healthy people.Circulating osteopontin in patients with AF could effectively predict the degree of atrial fibrosis.Conclusion: We found that osteopontin promoted atrial fibrosis by activating Akt/GSK-3?/?-catenin pathway and suppressing autophagy.Osteopontin could be a predictor of atrial fibrosis and a candidate target for improving therapies for AF.