MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension

Deng, L. et al. (2015) MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension. Circulation Research, 117(10), pp. 870-883. (doi:10.1161/CIRCRESAHA.115.306806) (PMID:26311719) (PMCID:PMC4620852)

Deng, L. et al. (2015) MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension. Circulation Research, 117(10), pp. 870-883. (doi:10.1161/CIRCRESAHA.115.306806) (PMID:26311719) (PMCID:PMC4620852)

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Abstract

Rationale: The pathogenesis of PAH remains unclear. The four 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 miRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signalling pathways, including estrogens receptor (ER), liver X factor/retinoic X receptor (LXR/RXR), TGF-β (Smads), and hypoxia (HRE) that regulated levels of all pri-miR stem loop transcription and resulting miRNA expression. We observed that miR-143-3p is selectively upregulated compared to 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 PASMCs-derived exosomes. Using assays with pulmonary arterial endothelial cells (PAECs) we demonstrated a paracrine pro-migratory and pro-angiogenic effect of miR-143-3p enriched exosomes from PASMC. Quantitative PCR and in situ hybridisation showed elevated expression of miR-143 in calf models of PAH as well as 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 for miR-143 in experimental PH in vivo in miR-143-/- and antimiR143-3p-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, while inhibition of miR-143-3p blocked experimental PH. Taken together these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret and Baker, Professor Andrew and Caudrillier, Dr Axelle and McBride, Dr Martin and White, Dr Kevin and Bradshaw, Dr Angela and Stevens, Dr Hannah and Blanco Lopez, Dr Francisco-Javie and Lu, Dr Ruifang and McClure, Dr John
Authors: Deng, L., Blanco Lopez, F. J., Stevens, H., Lu, R., Caudrillier, A., McBride, M., McClure, J. D., Grant, J., Thomas, M., Frid, M., Stenmark, K., White, K., Seto, A. G., Morrell, N. W., Bradshaw, A. C., MacLean, M. R., and Baker, A. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Circulation Research
Publisher:American Heart Association
ISSN:0009-7330
ISSN (Online):1524-4571
Published Online:26 August 2015
Copyright Holders:Copyright © 2016 American Heart Association
First Published:First published in Circulation Research 117(10):870-883
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
597901Development of MiR145 Antagonism as a novel Therapeutic strategy for Application to the treatment of pulmonary arterial hypertension.Andrew BakerBritish Heart Foundation (BHF)SP/12/9/29593RI CARDIOVASCULAR & MEDICAL SCIENCES
583361BHF Chair of Translational Cardiovascular SciencesAndrew BakerBritish Heart Foundation (BHF)CH/11/2/28733RI CARDIOVASCULAR & MEDICAL SCIENCES