title: Loss of microRNA-17∼92 in smooth muscle cells attenuates experimental pulmonary hypertension via induction of PDZ and LIM domain 5.
abstract: BACKGROUND
  Recent studies suggest that microRNAs (miRNAs) play important roles in regulation of pulmonary artery smooth muscle cell (PASMC) phenotype and are implicated in pulmonary arterial hypertension (PAH). However, the underlying molecular mechanisms remain elusive.
  
  
  OBJECTIVE
  This study aims to understand the mechanisms regulating PASMC proliferation and differentiation by microRNA-17∼92 (miR-17∼92) and to elucidate its implication in PAH.
  
  
  METHODS
  We generated smooth muscle cell (SMC)-specific miR-17∼92 and PDZ and LIM domain 5 (PDLIM5) knockout mice and overexpressed miR-17∼92 and PDLIM5 by injection of miR-17∼92 mimics or PDLIM5-V5-His plasmids and measured their responses to hypoxia. We used miR-17∼92 mimics, inhibitors, overexpression vectors, small interfering RNAs against PDLIM5, Smad, and transforming growth factor (TGF)-β to determine the role of miR-17∼92 and its downstream targets in PASMC proliferation and differentiation.
  
  
  RESULTS
  We found that human PASMC (HPASMC) from patients with PAH expressed decreased levels of the miR-17∼92 cluster, TGF-β, and SMC markers. Overexpression of miR-17∼92 increased and restored the expression of TGF-β3, Smad3, and SMC markers in HPASMC of normal subjects and patients with idiopathic PAH, respectively. Knockdown of Smad3 but not Smad2 prevented miR-17∼92-induced expression of SMC markers. SMC-specific knockout of miR-17∼92 attenuated hypoxia-induced pulmonary hypertension (PH) in mice, whereas reconstitution of miR-17∼92 restored hypoxia-induced PH in these mice. We also found that PDLIM5 is a direct target of miR-17/20a, and hypertensive HPASMC and mouse PASMC expressed elevated PDLIM5 levels. Suppression of PDLIM5 increased expression of SMC markers and enhanced TGF-β/Smad2/3 activity in vitro and enhanced hypoxia-induced PH in vivo, whereas overexpression of PDLIM5 attenuated hypoxia-induced PH.
  
  
  CONCLUSIONS
  We provided the first evidence that miR-17∼92 inhibits PDLIM5 to induce the TGF-β3/SMAD3 pathway, contributing to the pathogenesis of PAH.
authors: 1 Department of Pediatrics.
authors: Tianji
authors: T
authors: Chen
authors: Guofei
authors: G
authors: Zhou
authors: Qiyuan
authors: Q
authors: Zhou
authors: Haiyang
authors: H
authors: Tang
authors: Joyce Christina F
authors: JC
authors: Ibe
authors: Hongqiang
authors: H
authors: Cheng
authors: Deming
authors: D
authors: Gou
authors: Ju
authors: J
authors: Chen
authors: Jason X-J
authors: JX
authors: Yuan
authors: J Usha
authors: JU
authors: Raj
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D006976:Hypertension, Pulmonary / Q000209:etiology*; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology*; D008840:Microfilament Proteins / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D015291:Transforming Growth Factors / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C510085:ENH protein, mouse; C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs; D008840:Microfilament Proteins; D015291:Transforming Growth Factors
keywords: PDLIM5; SMAD3; microRNA-17∼92; pulmonary arterial hypertension; transforming growth factor-β3
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