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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 Al Ghouleh, I 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). e0153780 - ?.

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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.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Sahoo, Ssas279@pitt.eduSAS279
Meijles, DN
Al Ghouleh, Iima6@pitt.eduIMA6
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, or Units > Vascular Medicine Institute
Date: 1 January 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
Page Range: e0153780 - ?
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: 22 May 2019 12:55
URI: http://d-scholarship.pitt.edu/id/eprint/28261

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