title: Regulation and function of miR-214 in pulmonary arterial hypertension.
abstract: Dysregulation of microRNAs (miRNAs) can contribute to the etiology of diseases, including pulmonary arterial hypertension (PAH). Here we investigated a potential role for the miR-214 stem loop miRNA and the closely linked miR-199a miRNAs in PAH. All 4 miRNAs were upregulated in the lung and right ventricle (RV) in mice and rats exposed to the Sugen (SU) 5416 hypoxia model of PAH. Further, expression of the miRNAs was increased in pulmonary artery smooth muscle cells exposed to transforming growth factor β1 but not BMP4. We then examined miR-214(-/-) mice exposed to the SU 5416 hypoxia model of PAH or normoxic conditions and littermate controls. There were no changes in RV systolic pressure or remodeling observed between the miR-214(-/-) and wild-type hypoxic groups. However, we observed a significant increase in RV hypertrophy (RVH) in hypoxic miR-214(-/-) male mice compared with controls. Further, we identified that the validated miR-214 target phosphatase and tensin homolog was upregulated in miR-214(-/-) mice. Thus, miR-214 stem loop loss leads to elevated RVH and may contribute to the heart failure associated with PAH.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom; Present affiliation: Queens Medical Research Institute, University of Edinburgh, Edinburgh.
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Stevens
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom; Present affiliation: Queens Medical Research Institute, University of Edinburgh, Edinburgh.
authors.forename: Lin
authors.initials: L
authors.lastname: Deng
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom; Present affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, 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; Present affiliation: Queens Medical Research Institute, University of Edinburgh, Edinburgh.
authors.forename: Karine
authors.initials: K
authors.lastname: Pinel
authors.affiliation: Novartis Pharmaceuticals, Frimley Business Park, Frimley, Camberley, Surrey, United Kingdom; Present affiliations: AstraZeneca Research and Development and Göteborgs Universitet, Vastra Gotaland County, Sweden.
authors.forename: Matthew
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Division of Respiratory Medicine, Department of Medicine, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
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; Present affiliation: Queens Medical Research Institute, University of Edinburgh, Edinburgh; These authors contributed equally to this work.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom; Present affiliation: Queens Medical Research Institute, University of Edinburgh, Edinburgh; These authors contributed equally to this work.
authors.forename: Laura
authors.initials: L
authors.lastname: Denby
keywords: Sugen 5416 hypoxia model; microRNA-199; right ventricular hypertrophy; transforming growth factor β1