Astragalus polysaccharide protects against cardiac injury in a tnnt2a mutant zebrafish model of dilated cardiomyopathy.

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 ranging from 15 to 50%, and is an important cause of sudden cardiac death and heart failure. Genetic factors play important roles 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, few specific drugs are currently 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 revealed the protective effect of APS on tnnt2a-mutant dilated cardiomyopathy.

Methods: The tnnt2a^-/- mutant zebrafish were used as a DCM model for comparison with the APS-treated group. The survival rate and the sinus venosus‒bulbus arteriosus (SV‒BA) distance were used to observe changes in cardiac output. Histopathological changes were observed via hematoxylin and eosin (HE) staining and TUNEL staining. The transcriptomes of the zebrafish in the DCM group and APS-treated group were investigated via RNA-seq. qRT‒PCR detection of apoptosis-related gene expression.

Results: We found that APS markedly increased the heart rate and ATP content, and significantly inhibited the level of cardiac tissue edema, which are essential for improving the survival rate of tnnt2a^-/-. Furthermore, APS modulates key muscle fiber-related genes (including ttnb and myom3) and significantly impacts multiple signaling pathways, including Rap1, PI3K-Akt, Jak-STAT, and Wnt signaling. The qRT‒PCR results revealed that APS decreased the expression of bax, caspase-3, and caspase-9 but increased the expression of bcl-2 in DCM zebrafish.

Conclusions: Our findings suggest that APS can improve the survival rate in dilated cardiomyopathy and has a positive protective effect on the myocardium in the tnnt2a mutant zebrafish model of DCM.