Journal article
The microRNA-204-5p inhibits APJ signalling and confers resistance to cardiac hypertrophy and dysfunction
Clinical and translational medicine, Vol.12(1), pp.e693-n/a
01/2022
DOI: 10.1002/ctm2.693
PMCID: PMC8777385
PMID: 35060347
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.
Details
- Title: Subtitle
- The microRNA-204-5p inhibits APJ signalling and confers resistance to cardiac hypertrophy and dysfunction
- Creators
- Ravinder Reddy Gaddam - University of IowaYoung-Rae Kim - University of IowaJulia S Jacobs - Roy J. and Lucille A. Carver College of MedicineJin-Young Yoon - University of IowaQiuxia Li - University of IowaAngela Cai - University of IowaHamsitha Shankaiahgari - University of IowaBarry London - University of IowaKaikobad Irani - University of IowaAjit Vikram - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- Clinical and translational medicine, Vol.12(1), pp.e693-n/a
- DOI
- 10.1002/ctm2.693
- PMID
- 35060347
- PMCID
- PMC8777385
- NLM abbreviation
- Clin Transl Med
- ISSN
- 2001-1326
- eISSN
- 2001-1326
- Grant note
- R01 HL115955 / NHLBI NIH HHS R01 HL147545 / NHLBI NIH HHS 18CDA34080125 / American Heart Association 828081 / American Heart Association 19POST34380127 / American Heart Association
- Language
- English
- Date published
- 01/2022
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984297502702771
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