The Mechanism Study Of LncRNA-Safe On Myocardial Fibrosis

The cardiovascular mortality reaches to 40%in our country,and nearly 50%of cardiovascular patients die of myocardial infarction,which bring serious public and economic burdens.Myocardial fibrosis is the most important cause of myocardial infarction.,and it has gradually been recognized as a new target for the prevention and treatment of myocardial fibrosis.Existing antifibrotic drugs can only delay the progression of the diseases but can not effectively prevent or reverse this disease.Long noncoding RNA(lncRNA)are closely related to the occurrence and development of cardiovascular diseases,and have a great applied prospect in clinical diagnosis and treatment.However,the function and mechanism for IncRNAs in myocardial fibrosis is still unclear.We use gene chip technology to screene IncRNAs that differentially express in myocardial fibrosis tissues and normal heart tissues.Throughing chip verification and bioinformatic analysis,the lncRNA-AK137033(named Safe)is eventually selected for tne further study.Our study found that lncRNA-Safe is enriched in myocardial infarction zone tissues,and its expressive level continues to increase from 5th to 28th day after myocardial infarction;Safe mainly expresses in myofibroblasts which are induced by TGF?;blocking Safe expression significantly inhibits the activation and proliferation of myofibroblasts,which in turn reduces the secretion of extracellular matrix proteins.Moreover,injecting shSafe virus in the infarct zone significantly decreases fibrosis area after myocardial infarction,and improves the cardiac function.Throughing molecular studies in vitro,it is found that lnCRNA-Safe and its neighboring gene Sfrp2 reversely complement each other on 3'-UTR;the binding force for that protein HuR binding to the RNA duplex is significantly higher than single-stranded;Knocking out Safe significantly inhibites the stability of Sfrp2 in the nucleus and down-regulates the expression of Sfrp2;blocking the expression of Sfrp2 also significantly inhibites the myofibroblast transformation which is induced by TGF-?,and reduces the deposition of extracellular collagen.Above results indicate that lncRNA-Safe mainly enhances the stability and expression of Sfrp2 by forming a complex with Sfrp2 and HuR,thereby promoting the transformation of myofibroblasts;secretion and deposition of collagen.The expressive level of Safe after myocardial infarction can effectively block myocardial fibrosis and improve cardiac function.