Abstract P132: MEF2C-MYOCD and Leiomodin1 Suppression by miRNA-214 Promotes Smooth Muscle Cell Phenotype Switching in Pulmonary Arterial Hypertension
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 differentiated contractile to a synthetic state contributes to disease progression. While SMC contractile phenotype is reportedly maintained by a MEF2C-Myocardin (MYOCD) transcription factor interplay, its molecular control is poorly understood. MicroRNAs (miRs) have emerged as modulators of many cellular processes and some evidence associates them to MEF2C-MYOCD signaling. It is, therefore, plausible that miRs can regulate the synthetic SMC phenotype. We hypothesized that suppression of SMC contractile phenotype in PAH is mediated by miR-214 via repression of signaling by MEF2C-MYOCD and downstream contractile proteins leiomodin1 and smoothelin. Using qRT-PCR, the levels of miR-214 expression were shown to be upregulated in pulmonary artery SMC (PASMCs) from PAH- vs. control human subjects as well as in commercially obtained human PASMC (hPASMCs) exposed to hypoxia (~1.5 fold, p<0.05). These increases in miR-214 were paralleled by downregulation of MEF2C, MYOCD, and SMC-specific contractile proteins, leiomodin1 and smoothelin. MicroRNA-214 overexpression mimicked the PAH profile, downregulating MEF2C (1.00±0.054 vs. 0.696±0.026, p<0.05) and leiomodin1 (1.00± 0.051 vs. 0.281±0.095, p<0.05) protein levels for control vs miR-214 mimic, respectively. Hypoxia significantly reduced expression of SMC-specific contractile proteins leiomodin1, calponin1 (~50%) and smoothelin (~30%), and miR-214 antagomiR abrogated this response. We also investigated whether miR-214 participates in the induction of hPASMC proliferation, and found that hypoxia-induced hPASMC proliferation was significantly attenuated by the anti-miR (~2-fold). Further, anti-miR-214 restored PAH-PASMCs to a contractile (~50% reversal of MEF2C and leiomodin1 expression) and less proliferative phenotype. Our data illustrate a key role for miR-214 in modulation of MEF2C-MYOCD-leiomodin1 signaling and suggest that an antagonist of miR-214 could mitigate SMC phenotype changes in vascular hyperproliferative disorders including PAH.
Author Disclosures: S. Sahoo: None. D.N. Meijles: None. I. Al Ghouleh: None. M. Tandon: None. E. Cifuentes-Pagano: None. J. Sembrat: None. M. Rojas: None. E.A. Goncharova: None. P.J. Pagano: None.
- © 2015 by American Heart Association, Inc.