The microRNA‐204‐5p inhibits APJ signalling and confers resistance to cardiac hypertrophy and dysfunction

Abstract

Background

MicroRNAs regulate cardiac hypertrophy development, which precedes and predicts the risk of heart failure. microRNA‐204‐5p (miR‐204) is well expressed in cardiomyocytes, but its role in developing cardiac hypertrophy and cardiac dysfunction (CH/CD) remains poorly understood.

Methods: We performed RNA‐sequencing, echocardiographic, and molecular/morphometric analysis of the heart of mice lacking or overexpressing miR‐204 five weeks after trans‐aortic constriction (TAC). The neonatal rat cardiomyocytes, H9C2, and HEK293 cells were used to determine the mechanistic role of miR‐204.

Results

The stretch induces miR‐204 expression, and miR‐204 inhibits the stretch‐induced hypertrophic response of H9C2 cells. The mice lacking miR‐204 displayed a higher susceptibility to CH/CD during pressure overload, which was reversed by the adeno‐associated virus serotype‐9‐mediated cardioselective miR‐204 overexpression. Bioinformatic analysis of the cardiac transcriptomics of miR‐204 knockout mice following pressure overload suggested deregulation of apelin‐receptor (APJ) signalling. We found that the stretch‐induced extracellular signal‐regulated kinase 1/2 (ERK1/2) activation and hypertrophy‐related genes expression depend on the APJ, and both of these effects are subject to miR‐204 levels. The dynamin inhibitor dynasore inhibited both stretch‐induced APJ endocytosis and ERK1/2 activation. In contrast, the miR‐204‐induced APJ endocytosis was neither inhibited by dynamin inhibitors (dynasore and dyngo) nor associated with ERK1/2 activation. We find that the miR‐204 increases the expression of ras‐associated binding proteins (e.g., Rab5a, Rab7) that regulate cellular endocytosis.

Conclusions

Our results show that miR‐204 regulates trafficking of APJ and confers resistance to pressure overload‐induced CH/CD, and boosting miR‐204 can inhibit the development of CH/CD.