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MEF2C-MYOCD and Leiomodin1 Suppression by miRNA-214 Promotes Smooth Muscle Cell Phenotype Switching in Pulmonary Arterial Hypertension.
Sahoo, Sanghamitra; Meijles, Daniel N; Al Ghouleh, Imad; Tandon, Manuj; Cifuentes-Pagano, Eugenia; Sembrat, John; Rojas, Mauricio; Goncharova, Elena; Pagano, Patrick J.
Afiliação
  • Sahoo S; Department of Pharmacology and Chemical Biology University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.
  • Meijles DN; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.
  • Al Ghouleh I; Department of Pharmacology and Chemical Biology University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.
  • Tandon M; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.
  • Cifuentes-Pagano E; Department of Pharmacology and Chemical Biology University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.
  • Sembrat J; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.
  • Rojas M; Department of Pharmacology and Chemical Biology University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.
  • Goncharova E; Department of Pharmacology and Chemical Biology University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.
  • Pagano PJ; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.
PLoS One ; 11(5): e0153780, 2016.
Article em En | MEDLINE | ID: mdl-27144530
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Artéria Pulmonar / Autoantígenos / Proteínas Nucleares / Transativadores / Proteínas do Citoesqueleto / Miócitos de Músculo Liso / MicroRNAs / Hipertensão Pulmonar Limite: Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Artéria Pulmonar / Autoantígenos / Proteínas Nucleares / Transativadores / Proteínas do Citoesqueleto / Miócitos de Músculo Liso / MicroRNAs / Hipertensão Pulmonar Limite: Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article