MiRNA-199a-5p influences pulmonary artery hypertension via downregulating Smad3

Biochem Biophys Res Commun. 2016 May 13;473(4):859-866. doi: 10.1016/j.bbrc.2016.03.140. Epub 2016 Mar 30.

Abstract

MicroRNAs (miRNAs) play important roles in pulmonary artery hypertension (PAH). Recently, it has been reported that miR-199a-5p participates in the progression of chronic obstructive pulmonary disease, ventricular hypertrophy and heart failure. However, the roles of miR-199a-5p in PAH are still unclear. In the present study, miR-199a-5p was investigated in PAH rat models and in human pulmonary artery smooth muscle cells (HPASMCs) and endothelial cells (HPAECs). The expression of miR-199a-5p was significantly increased following PAH induction, and anti-miR-199a-5p could increase the nitric oxide (NO) level and decrease the PAH-induced upregulation of pulmonary artery pressure and right ventricular hypertrophy. Moreover, in HPASMCs and HPAECs, miR-199a-5p overexpression could inhibit the level of NO and promote the concentration of Ca(2+), but anti-miR-199a-5p showed opposite results. Further analysis demonstrated that miR-199a-5p attenuated the expression of Smad3. Importantly, Smad3 was confirmed to be the target gene of miR-199a-5p using dual-luciferase reporter assay. Mechanism analyses revealed that the downregulation of NO and the upregulation of Ca(2+) caused by miR-199a-5p were all reversed by Smad3 overexpression in HPASMCs and HPAECs. Moreover, in PAH model, Smad3, p-Smad3 and Smad4 were all downregulated in lung tissues, and SIS3 (Smad3 inhibitor) could reverse the effects of anti-miR-199a-5p in PAH rats. Our date suggest that miR-199a-5p may function as a regulator of PAH by targeting Smad3, indicating a novel therapeutic strategy for patients with PAH.

Keywords: Calcium concentration; Nitric oxide; Pulmonary artery hypertension; Smad3; miR-199a-5p.

MeSH terms

  • Animals
  • Calcium / metabolism
  • Down-Regulation*
  • Humans
  • Hypertension, Pulmonary / genetics*
  • Hypertension, Pulmonary / physiopathology
  • Lung / physiopathology*
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Nitric Oxide / metabolism
  • Pulmonary Artery / physiopathology*
  • Rats
  • Rats, Sprague-Dawley
  • Smad3 Protein / genetics*
  • Smad3 Protein / metabolism*
  • Tissue Distribution

Substances

  • MicroRNAs
  • SMAD3 protein, human
  • Smad3 Protein
  • mirn199 microRNA, human
  • Nitric Oxide
  • Calcium