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  • The microRNA-204-5p inhibits APJ signalling and confers resistance to cardiac hypertrophy and dysfunction.

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

Clinical and translational medicine (2022-01-22)
Ravinder Reddy Gaddam, Young-Rae Kim, Julia S Jacobs, Jin-Young Yoon, Qiuxia Li, Angela Cai, Hamsitha Shankaiahgari, Barry London, Kaikobad Irani, Ajit Vikram
ABSTRACT

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. 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. 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. 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.

MATERIALS
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Product Description

Sigma-Aldrich
Anti-Apelin receptor Antibody, from rabbit, purified by affinity chromatography