title: Transient but not genetic loss of miR-451 is protective in the development of pulmonary arterial hypertension.
abstract: MicroRNAs are small noncoding RNAs involved in the regulation of gene expression and have recently been implicated in the development of pulmonary arterial hypertension (PAH). Previous work has established that miR-451 is upregulated in rodent models of PAH. 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 PAH. Silencing of miR-451 was performed in vivo using miR-451 knockout mice and an anti-miR targeting mature miR-451 in rats. Coupled with exposure to hypoxia, indices of PAH were assessed. The effect of modulating miR-451 on human pulmonary artery smooth muscle cell proliferation and migration was analyzed. We observed a reduction in systolic right ventricular pressure in hypoxic rats pretreated with anti-miR-451 compared with hypoxia alone ([Formula: see text] mmHg and [Formula: see text] mmHg, respectively; [Formula: see text]). In miR-451 knockout mice, compared with wild-type hypoxic mice, no significant differences were observed following exposure to chronic hypoxia. In vitro analysis demonstrated that overexpression of miR-451 in human pulmonary artery smooth muscle cells promoted migration under serum-free conditions. No effect on cellular proliferation was observed. In conclusion, transient inhibition of miR-451 attenuated the development of PAH in hypoxia-exposed rats. Genetic deletion of miR-451 had no beneficial effect on indices of PAH, potentially because of pathway redundancy compensating for the loss of miR-451.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Grant
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Morecroft
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Dempsie
authors.affiliation: miRagen Therapeutics, Boulder, Colorado, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: van Rooij
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: MacLean
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
keywords: hypoxia; microRNA; migration; pulmonary vascular disorder; smooth muscle cell