Protection role of Astragalus polysaccharide against Cardiac injury in tnnt2a mutant Zebrafish model of Dilated Cardiomyopathy

Abstract

Abstract Background Dilated cardiomyopathy(DCM) is a severe and irreversible heart disease characterized by dilated ventricles and decreased myocardial function. DCM has a poor prognosis and a very low survival rate, with a 5-year mortality rate of 15–50%, and is an important cause of sudden cardiac death and heart failure.Genetic factors play an important role in the pathogenesis of DCM. Mutations in the cardiac troponin T (tnnt2) gene represent an important subset of known pathogenic variants that bind to DCM. However, there are currently few specific drugs available to treat DCM caused by these gene mutations. Astragalus polysaccharide (APS), the main active ingredient of Astragalus mongholicus Bunge(Huangqi), is widely used in China to treat cardiovascular diseases, including DCM. This study explored drugs for the treatment of DCM caused by tnnt2a mutation and found the protective effect of Astragalus polysaccharide on tnnt2a-mutant dilated cardiomyopathy.Methods The tnnt2a-/- mutant zebrafish was used as a DCM model to compare with the APS-administered group. Counting the survival rate and measuring the sinus venosus-bulbus arteriosus (SV-BA) distance to observe changes in cardiac output.Histopathological changes were observed with hematoxylin and eosin (HE) staining and Tunel staining.Transcriptomes of zebrafish DCM group and APS-treated group were investigated by RNA-seq method. qRT-PCR detection of apoptosis-related genes expression.Results We found that APS markedly increased the heart rate and ATP content,significantly inhibited the level of cardiac tissue edema,which are essential for improving survival rate in tnnt2a-/- zebrafish.Moreover,APS interfere some key genes related to muscle fibers,such as titin b (ttnb)and myomesin 3 (myom3),APS intervention significantly participated in Rap1 signaling pathway,PI3K-Akt signaling pathway,Jak-STAT signaling pathway,Wnt signaling pathway.The qRT-PCR results revealed that APS decreased the expression of Bax,Caspase-3,Caspase-9 but incresaed the expression of Bcl-2 in DCM zebrafish.Conclusions Our findings suggest that APS could improve survival rate in Dilated Cardiomyopathy, and has a positive protective effect on the myocardium in the tnnt2a mutant zebrafish model of DCM.