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Transient but not genetic loss of miR-451 is protective in the development of pulmonary arterial hypertension

Lookup NU author(s): Dr Jenny Grant


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MicroRNAs are small noncoding RNAs involved in the regulation of gene expression and haverecently been implicated in the development of pulmonary arterial hypertension (PAH). Previous work hasestablished that miR-451 is upregulated in rodent models of PAH. The role of miR-451 in the pulmonarycirculation is unknown. We therefore sought to assess the involvement of miR-451 in the development ofPAH. Silencing of miR-451 was performed in vivo using miR-451 knockout mice and an anti-miR targetingmature miR-451 in rats. Coupled with exposure to hypoxia, indices of PAH were assessed. The effect ofmodulating 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 (47:7  1:36 mmHg and 56:0  2:03 mmHg, respectively; P < :01). InmiR-451 knockout mice, compared with wild-type hypoxic mice, no significant differences were observedfollowing exposure to chronic hypoxia. In vitro analysis demonstrated that overexpression of miR-451 inhuman pulmonary artery smooth muscle cells promoted migration under serum-free conditions. No effect oncellular proliferation was observed. In conclusion, transient inhibition of miR-451 attenuated the developmentof 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.

Publication metadata

Author(s): Grant JS, Morecroft I, Dempsie Y, vanRooij E, MacLean MR, Baker AH

Publication type: Article

Publication status: Published

Journal: Pulmonary Circulation

Year: 2013

Volume: 3

Issue: 4

Pages: 840-850

Print publication date: 01/12/2013

Online publication date: 03/02/2014

Acceptance date: 28/09/2013

ISSN (print): 2045-8932

ISSN (electronic): 2045-8940

Publisher: Pulmonary Vascular Research Institute



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