Transient but not genetic loss of miR-451 attenuates the development of pulmonary arterial hypertension

Grant, J. S., Morecroft, I., Dempsie, Y., van Rooij, E., MacLean, M. R. and Baker, A. H. (2013) Transient but not genetic loss of miR-451 attenuates the development of pulmonary arterial hypertension. Pulmonary Circulation, 3(4), pp. 840-850. (doi: 10.1086/674751) (PMID:25006399) (PMCID:PMC4070830)

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Abstract

<b>Rationale:</b> MicroRNAs are small non-coding RNAs involved in the regulation of gene expression and have recently been implicated in the development of pulmonary arterial hypertension (PAH). Previous work established that miR-451 is up-regulated in rodent models of PAH.<p></p> <b>Objectives:</b> The role of miR-451 in the pulmonary circulation is unknown. We therefore sought to assess the involvement of miR-451 in the development of pulmonary arterial hypertension.<p></p> <b>Methods:</b> Silencing of miR-451 was performed in vivo using miR-451 knockout mice and an antimiR targeting mature miR-451 in rats. Coupled with exposure to hypoxia, indices of pulmonary arterial hypertension were assessed. The effect of modulating miR-451 on human pulmonary artery smooth muscle cell proliferation and migration was analysed.<p></p> <b>Measurements and Main Results:</b> We observed a reduction in systolic right ventricular pressure in hypoxic rats pre-treated with antimiR-451 compared to hypoxia alone (47.7 ± 1.36mmHg and 56.0 ± 2.03mmHg respectively, p<0.01). In miR-451 knockout mice following exposure to chronic hypoxia, no significant differences were observed compared to wild type hypoxic mice. In vitro analysis demonstrated that over-expression of miR-451 in human pulmonary artery smooth muscle cells promoted migration under serum-free conditions. No effect on cellular proliferation was observed.<p></p> <b>Conclusions:</b> Transient inhibition of miR-451 attenuated the development of pulmonary arterial hypertension in hypoxia exposed rats. Genetic deletion of miR-451 had no beneficial effect on indices of pulmonary arterial hypertension, potentially due to pathway redundancy compensating for the loss of miR-451.<p></p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret and Baker, Professor Andrew and Dempsie, Dr Yvonne and Morecroft, Dr Ian
Authors: Grant, J. S., Morecroft, I., Dempsie, Y., van Rooij, E., MacLean, M. R., and Baker, A. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Pulmonary Circulation
Publisher:Medknow Publications
ISSN:2045-8932
ISSN (Online):2045-8940
Copyright Holders:Copyright © 2013 Medknow Publications
First Published:First published in Pulmonary Circulation 3(4):840-850
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
513102In Vivo capacity building studentshipsMargaret MacleanMedical Research Council (MRC)G1000389-2/1RI CARDIOVASCULAR & MEDICAL SCIENCES
547851Micro RNA and their role in vascular remodelling associated with the development of pulmonary arterial hypertensionAndrew BakerBritish Heart Foundation (BHF)SP/10/7/28383RI CARDIOVASCULAR & MEDICAL SCIENCES