Journal
CLINICAL AND TRANSLATIONAL MEDICINE
Volume 12, Issue 1, Pages -Publisher
JOHN WILEY & SONS LTD
DOI: 10.1002/ctm2.693
Keywords
apelin-receptor; aplnr; ERK1; 2; heart failure; microRNA-204; noncoding RNAs
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Funding
- American Heart Association [18CDA34080125, 19POST34380127, 828081]
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This study reveals that miR-204 regulates cardiac hypertrophy development and overexpression of miR-204 can inhibit the development of cardiac dysfunction caused by hypertrophy.
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.
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