miR-21 Promotes Fibrogenic Epithelial-to-Mesenchymal Transition of Epicardial Mesothelial Cells Involving Programmed Cell Death 4 and Sprouty-1
Open Access
- 18 February 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (2), e56280
- https://doi.org/10.1371/journal.pone.0056280
Abstract
The lining of the adult heart contains epicardial mesothelial cells (EMCs) that have the potential to undergo fibrogenic Epithelial-to-Mesenchymal Transition (EMT) during cardiac injury. EMT of EMCs has therefore been suggested to contribute to the heterogeneous fibroblast pool that mediates cardiac fibrosis. However, the molecular basis of this process is poorly understood. Recently, microRNAs (miRNAs) have been shown to regulate a number of sub-cellular events in cardiac disease. Hence, we hypothesized that miRNAs regulate fibrogenic EMT in the adult heart. Indeed pro-fibrogenic stimuli, especially TGF-β, promoted EMT progression in EMC cultures, which resulted in differential expression of numerous miRNAs, especially the pleiotropic miR-21. Accordingly, ectopic expression of miR-21 substantially promoted the fibroblast-like phenotype arising from fibrogenic EMT, whereas an antagonist that targeted miR-21 blocked this effect, as assessed on the E-cadherin/α-smooth muscle actin balance, cell viability, matrix activity, and cell motility, thus making miR-21 a relevant target of EMC-derived fibrosis. Several mRNA targets of miR-21 was differentially regulated during fibrogenic EMT of EMCs and miR-21-dependent targeting of Programmed Cell Death 4 (PDCD4) and Sprouty Homolog 1 (SPRY1) significantly contributed to the development of a fibroblastoid phenotype. However, PDCD4- and SPRY1-targeting was not entirely ascribable to all phenotypic effects from miR-21, underscoring the pleiotropic biological role of miR-21 and the increasing number of recognized miR-21 targets.This publication has 63 references indexed in Scilit:
- Unique MicroRNA Profile in End-stage Heart Failure Indicates Alterations in Specific Cardiovascular Signaling NetworksOnline Journal of Public Health Informatics, 2009
- MicroRNA Expression Signature and the Role of MicroRNA-21 in the Early Phase of Acute Myocardial InfarctionOnline Journal of Public Health Informatics, 2009
- MicroRNA-21 protects against the H2O2-induced injury on cardiac myocytes via its target gene PDCD4Journal of Molecular and Cellular Cardiology, 2009
- The role of IL-1 in the pathogenesis of heart diseaseArchivum Immunologiae et Therapiae Experimentalis, 2009
- MicroRNAs: Target Recognition and Regulatory FunctionsCell, 2009
- Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosisProceedings of the National Academy of Sciences of the United States of America, 2008
- Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heartNature, 2008
- SMAD proteins control DROSHA-mediated microRNA maturationNature, 2008
- Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophyJournal of Molecular and Cellular Cardiology, 2007
- A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failureProceedings of the National Academy of Sciences of the United States of America, 2006