miR-143 and miR-145 promote hypoxia-induced proliferation and migration of pulmonary arterial smooth muscle cells through regulating ABCA1 expression

Cardiovasc Pathol. 2018 Nov-Dec:37:15-25. doi: 10.1016/j.carpath.2018.08.003. Epub 2018 Aug 23.

Abstract

Background: Excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) play an important role in the occurrence and development of pulmonary arterial hypertension (PAH). miR-143/145 was reported to be up-regulated in the animal models and PAH patients, and deletion of miR-143/145 cluster prevented the development of hypoxia-induced pulmonary hypertension, but its underlying mechanism has not been elucidated.

Methods: qRT-PCR and Western blot were performed to detect the expressions of miR-143/145 and ATP-binding cassette transporter A1 (ABCA1) in PAH patients and PASMCs under hypoxic conditions. Cell proliferation and migration were assessed by Cell Counting Kit-8 and wound-healing assay, respectively. Luciferase reporter assay and RNA immunoprecipitation were conducted to confirm the interaction between miR-143/145 and ABCA1. Hypoxia-induced PAH rat model was established to confirm the functions of miR-143/145 in the pathogenesis of PAH and its underlying mechanism in vivo.

Results: miR-143 and miR-145 were up-regulated and ABCA1 was down-regulated in PAH patients and PASMCs under hypoxic conditions for different time, as well as hypoxia-induced PAH rats. miR-143/145 inhibition and ABCA1 overexpression suppressed hypoxia-induced proliferation and migration in PASMCs. ABCA1 was identified as a direct target of miR-143/145 in PASMCs. Moreover, ABCA1 partially reversed miR-143/145-mediated promotion of hypoxia-induced cell proliferation and migration in PASMCs. Furthermore, in vivo experiments confirmed that inhibition of miR-143/145 prevents hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling by targeting ABCA1.

Conclusion: miR-143/145 promoted hypoxia-induced proliferation and migration of PASMCs by targeting ABCA1, contributing to better understanding of the mechanism underlying the pathogenesis of PAH.

Keywords: ABCA1; Hypoxia; Pulmonary arterial hypertension; Pulmonary artery smooth muscle cells; miR-143/145.

MeSH terms

  • ATP Binding Cassette Transporter 1 / genetics
  • ATP Binding Cassette Transporter 1 / metabolism*
  • Adult
  • Animals
  • Case-Control Studies
  • Cell Hypoxia
  • Cell Movement*
  • Cell Proliferation*
  • Disease Models, Animal
  • Familial Primary Pulmonary Hypertension / genetics
  • Familial Primary Pulmonary Hypertension / metabolism*
  • Familial Primary Pulmonary Hypertension / pathology
  • Familial Primary Pulmonary Hypertension / physiopathology
  • Female
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Hypoxia / genetics
  • Hypoxia / metabolism
  • Hypoxia / pathology
  • Hypoxia / physiopathology
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Middle Aged
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • Muscle, Smooth, Vascular / physiopathology
  • Myocytes, Smooth Muscle / metabolism*
  • Myocytes, Smooth Muscle / pathology
  • Pulmonary Artery / metabolism
  • Pulmonary Artery / pathology
  • Pulmonary Artery / physiopathology
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Vascular Remodeling

Substances

  • ABCA1 protein, human
  • ABCA1 protein, rat
  • ATP Binding Cassette Transporter 1
  • MIRN143 microRNA, human
  • MIRN143 microRNA, rat
  • MIRN145 microRNA, human
  • MIRN145 microRNA, rat
  • MicroRNAs