MicroRNA-143 Activation Regulates Smooth Muscle and Endothelial Cell Crosstalk in Pulmonary Arterial Hypertension

Lin Deng, Francisco J. Blanco, Hannah Stevens, Ruifang Lu, Axelle Caudrillier, Martin McBride, John D. McClure, Jenny Grant, Matthew Thomas, Maria Frid, Kurt Stenmark, Kevin White, Anita G. Seto, Nicholas W. Morrell, Angela C. Bradshaw, Margaret R. MacLean, Andrew H. Baker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

244 Citations (Scopus)

Abstract

Rationale: The pathogenesis of pulmonary arterial hypertension (PAH) remains unclear. The 4 microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered. Objective: To elucidate the transcriptional regulation of the miR-143/145 cluster and the role of miR-143 in PAH. Methods and Results: We identified the promoter region that regulates miR-143/145 microRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signaling pathways, including estrogen receptor, liver X factor/retinoic X receptor, transforming growth factor-β (Smads), and hypoxia (hypoxia response element), that regulated levels of all pri-miR stem loop transcription and resulting microRNA expression. We observed that miR-143-3p is selectively upregulated compared with miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMC-derived exosomes. Using assays with pulmonary arterial endothelial cells, we demonstrated a paracrine promigratory and proangiogenic effect of miR-143-3p-enriched exosomes from PASMC. Quantitative polymerase chain reaction and in situ hybridization showed elevated expression of miR-143 in calf models of PAH and in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role of miR-143 in experimental pulmonary hypertension in vivo in miR-143-/-and anti-miR-143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings. Conclusions: MiR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, whereas inhibition of miR-143-3p blocked experimental pulmonary hypertension. Taken together, these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology.

Original languageEnglish
Pages (from-to)870-883
Number of pages14
JournalCirculation Research
Volume117
Issue number10
DOIs
Publication statusPublished - 1 Jan 2015

Keywords

  • cell movement
  • endothelium
  • exosomes
  • hypertension, pulmonary
  • microRNAs
  • myocytes, smooth muscle

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