title: miR-21 promotes fibrogenic epithelial-to-mesenchymal transition of epicardial mesothelial cells involving Programmed Cell Death 4 and Sprouty-1.
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.
authors: Laboratory for Molecular and Cellular Cardiology, Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
authors: Hasse
authors: H
authors: Brønnum
authors: Ditte C
authors: DC
authors: Andersen
authors: Mikael
authors: M
authors: Schneider
authors: Maria B
authors: MB
authors: Sandberg
authors: Tilde
authors: T
authors: Eskildsen
authors: Solveig B
authors: SB
authors: Nielsen
authors: Raghu
authors: R
authors: Kalluri
authors: Søren P
authors: SP
authors: Sheikh
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D016000:Cluster Analysis; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005355:Fibrosis / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium; D010496:Pericardium / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C524940:MIRN21 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C114487:PDCD4 protein, human; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; C486055:SPRY1 protein, human