A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples

Paola Caruso, Yvonne Dempsie, Hannah C Stevens, Robert A McDonald, Lu Long, Ruifang Lu, Kevin White, Kirsty M Mair, John D McClure, Mark Southwood, Paul Upton, Mei Xin, Eva van Rooij, Eric N Olson, Nicholas W Morrell, Margaret R MacLean, Andrew H Baker

Research output: Contribution to journalArticlepeer-review

Abstract

RATIONALE: Despite improved understanding of the underlying genetics, pulmonary arterial hypertension (PAH) remains a severe disease. Extensive remodeling of small pulmonary arteries, including proliferation of pulmonary artery smooth muscle cells (PASMCs), characterizes PAH. MicroRNAs (miRNAs) are noncoding RNAs that have been shown to play a role in vascular remodeling.

OBJECTIVE: We assessed the role of miR-145 in PAH.

METHODS AND RESULTS: We localized miR-145 in mouse lung to smooth muscle. Using quantitative PCR, we demonstrated increased expression of miR-145 in wild-type mice exposed to hypoxia. PAH was evaluated in miR-145 knockout and mice treated with anti-miRs via measurement of systolic right ventricular pressure, right ventricular hypertrophy, and percentage of remodeled pulmonary arteries. miR-145 deficiency and anti-miR-mediated reduction resulted in significant protection from the development of PAH. In contrast, miR-143 anti-miR had no effect. Furthermore, we observed upregulation of miR-145 in lung tissue of patients with idiopathic and heritable PAH compared with unaffected control subjects and demonstrated expression of miR-145 in SMC of remodeled vessels from such patients. Finally, we show elevated levels of miR-145 expression in primary PASMCs cultured from patients with BMPR2 mutations and also in the lungs of BMPR2-deficient mice.

CONCLUSIONS: miR-145 is dysregulated in mouse models of PAH. Downregulation of miR-145 protects against the development of PAH. In patient samples of heritable PAH and idiopathic PAH, miR-145 is expressed in remodeled vessels and mutations in BMPR2 lead to upregulation of miR-145 in mice and PAH patients. Manipulation of miR-145 may represent a novel strategy in PAH treatment.

Original languageEnglish
Pages (from-to)290-300
Number of pages11
JournalCirculation Research
Volume111
Issue number3
DOIs
Publication statusPublished - 20 Jul 2012

Keywords

  • Animals
  • Disease Models, Animal
  • Down-Regulation
  • Female
  • Gene Knock-In Techniques
  • Humans
  • Hypertension, Pulmonary
  • Lung
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs

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