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MEF2c-MyoCD and Leiomodin1 suppression by miRNA-214 promotes smooth muscle cell phenotype switching in pulmonary arterial hypertension

Sahoo, S and Meijles, DN and Ghouleh, IA and Tandon, M and Cifuentes-Pagano, E and Sembrat, J and Rojas, M and Goncharova, E and 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).

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Abstract

© 2016 Sahoo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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 MEF2Cmyocardin (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.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Sahoo, Ssas279@pitt.eduSAS279
Meijles, DN
Ghouleh, IA
Tandon, Mmat137@pitt.eduMAT137
Cifuentes-Pagano, E
Sembrat, Jjcs75@pitt.eduJCS75
Rojas, Mmar176@pitt.eduMAR176
Goncharova, EEAG59@pitt.eduEAG59
Pagano, PJpagano@pitt.eduPAGANO
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorXiao, QingzhongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, Offices, or Units > Vascular Medicine Institute
Date: 1 May 2016
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 11
Number: 5
DOI or Unique Handle: 10.1371/journal.pone.0153780
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Critical Care Medicine
School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
Date Deposited: 31 Aug 2016 18:08
Last Modified: 16 May 2020 09:55
URI: http://d-scholarship.pitt.edu/id/eprint/28261

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