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Circ Res. 2015 Oct 23;117(10):870-883. doi: 10.1161/CIRCRESAHA.115.306806. Epub 2015 Aug 26.

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

Author information

1
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
2
King's British Heart Foundation Centre, King's College London, 125 Coldharbour Lane, London SE59NU, United Kingdom.
3
Novartis Institutes for BioMedical Research, Horsham UK.
4
AstraZeneca R&D Mölndal, R&D | Respiratory, Inflammation and Autoimmunity (RIA) Innovative Medicines, Building AC461, SE-431 83 Mölndal, Sweden.
5
Division of Critical Care Medicine/Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics and Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
6
Novartis Institutes for BioMedical Research, Inc.,250 Massachusetts Avenue, Cambridge, MA 02139, United States.
7
MiRagen Therapeutics, Inc, Boulder, CO.
8
Division of Respiratory Medicine, Department of Medicine, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UK.
#
Contributed equally

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.

KEYWORDS:

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

PMID:
26311719
PMCID:
PMC4620852
DOI:
10.1161/CIRCRESAHA.115.306806
[Indexed for MEDLINE]
Free PMC Article

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