Sahoo, S; Meijles, DN; Al Ghouleh, I; Tandon, M; Cifuentes-Pagano, E; Sembrat, J; Rojas, M; Goncharova, E; Pagano, PJ
(2016)
MEF2C-MYOCD and Leiomodin1 Suppression by miRNA-214 Promotes Smooth Muscle Cell Phenotype Switching in Pulmonary Arterial Hypertension.
PLoS One, 11 (5).
e0153780.
ISSN 1932-6203
https://doi.org/10.1371/journal.pone.0153780
SGUL Authors: Meijles, Daniel Nathan
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Abstract
BACKGROUND: Vascular hyperproliferative disorders are characterized by excessive smooth muscle cell (SMC) proliferation leading to vessel remodeling and occlusion. In pulmonary arterial hypertension (PAH), SMC phenotype switching from a terminally differentiated contractile to synthetic state is gaining traction as our understanding of the disease progression improves. While maintenance of SMC contractile phenotype is reportedly orchestrated by a MEF2C-myocardin (MYOCD) interplay, little is known regarding molecular control at this nexus. Moreover, the burgeoning interest in microRNAs (miRs) provides the basis for exploring their modulation of MEF2C-MYOCD signaling, and in turn, a pro-proliferative, synthetic SMC phenotype. We hypothesized that suppression of SMC contractile phenotype in pulmonary hypertension is mediated by miR-214 via repression of the MEF2C-MYOCD-leiomodin1 (LMOD1) signaling axis. METHODS AND RESULTS: In SMCs isolated from a PAH patient cohort and commercially obtained hPASMCs exposed to hypoxia, miR-214 expression was monitored by qRT-PCR. miR-214 was upregulated in PAH- vs. control subject hPASMCs as well as in commercially obtained hPASMCs exposed to hypoxia. These increases in miR-214 were paralleled by MEF2C, MYOCD and SMC contractile protein downregulation. Of these, LMOD1 and MEF2C were directly targeted by the miR. Mir-214 overexpression mimicked the PAH profile, downregulating MEF2C and LMOD1. AntagomiR-214 abrogated hypoxia-induced suppression of the contractile phenotype and its attendant proliferation. Anti-miR-214 also restored PAH-PASMCs to a contractile phenotype seen during vascular homeostasis. CONCLUSIONS: Our findings illustrate a key role for miR-214 in modulation of MEF2C-MYOCD-LMOD1 signaling and suggest that an antagonist of miR-214 could mitigate SMC phenotype changes and proliferation in vascular hyperproliferative disorders including PAH.
Item Type: | Article | ||||||||||||
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Additional Information: | © 2016 Sahoo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | ||||||||||||
Keywords: | General Science & Technology, MD Multidisciplinary | ||||||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Vascular (INCCVA) |
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Journal or Publication Title: | PLoS One | ||||||||||||
ISSN: | 1932-6203 | ||||||||||||
Language: | eng | ||||||||||||
Publisher License: | Creative Commons: Attribution 4.0 | ||||||||||||
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PubMed ID: | 27144530 | ||||||||||||
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URI: | https://openaccess.sgul.ac.uk/id/eprint/108894 | ||||||||||||
Publisher's version: | https://doi.org/10.1371/journal.pone.0153780 |
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