MEF2C-MYOCD and Leiomodin1 Suppression by miRNA-214 Promotes Smooth Muscle Cell Phenotype Switching in Pulmonary Arterial Hypertension.
MEF2C-MYOCD and Leiomodin1 Suppression by miRNA-214 Promotes Smooth Muscle Cell Phenotype Switching in Pulmonary Arterial Hypertension.
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DOI：
10.1371/journal.pone.0153780
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Pagano PJ
中科院分区：
文献类型：
--
作者：
Sahoo S;Meijles DN;Al Ghouleh I;Tandon M;Cifuentes-Pagano E;Sembrat J;Rojas M;Goncharova E;Pagano PJ
血管过度增殖性疾病的特征在于平滑肌细胞（SMC）过度增殖，导致血管重塑和闭塞。在肺动脉高压（PAH）中，SMC表型从终末分化的收缩状态转换为合成状态，随着我们对疾病进展的理解的提高而获得牵引力。虽然据报道SMC收缩表型的维持是由MEF 2C-心肌蛋白（MYOCD）相互作用协调的，但关于该关系的分子控制知之甚少。此外，对微小RNA（miR）的新兴兴趣为探索其对MEF 2C-MYOCD信号传导的调节以及进而对促增殖合成SMC表型的调节提供了基础。我们假设肺动脉高压中SMC收缩表型的抑制是由miR-214通过抑制MEF 2C-MYOCD-leiomodin 1（LMOD 1）信号轴介导的。在从PAH患者队列分离的SMC和暴露于缺氧的市售hPASMC中，通过qRT-PCR监测miR-214表达。miR-214在PAH-与对照受试者hPASMC以及暴露于缺氧的市售hPASMC中上调。miR-214的这些增加被MEF 2C、MYOCD和SMC收缩蛋白下调所抵消。其中，LMOD 1和MEF 2C被miR直接靶向。Mir-214过表达模拟PAH谱，下调MEF 2C和LMOD 1。AntagomiR-214消除了缺氧诱导的收缩表型抑制及其伴随的增殖。抗miR-214还使PAH-PASMC恢复到血管稳态期间观察到的收缩表型。我们的研究结果说明了miR-214在调节MEF 2C-MYOCD-LMOD 1信号传导中的关键作用，并表明miR-214的拮抗剂可以减轻血管过度增殖性疾病（包括PAH）中SMC表型变化和增殖。
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. 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. 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.