title: Featured Article: microRNA-125a in pulmonary hypertension: Regulator of a proliferative phenotype of endothelial cells.
abstract: Vascular remodeling due to excessive proliferation of endothelial and smooth muscle cells is a hallmark feature of pulmonary hypertension. microRNAs (miRNAs) are a class of small, non-coding RNA fragments that have recently been associated with remodeling of pulmonary arteries, in particular by silencing the bone morphogenetic protein receptor type II (BMPR2). Here we identified a novel pathway involving the concerted action of miR-125a, BMPR2 and cyclin-dependent kinase inhibitors (CDKN) that controls a proliferative phenotype of endothelial cells. An in silico approach predicted miR-125a to target BMPR2. Functional inhibition of miR-125a resulted in increased proliferation of these cells, an effect that was found accompanied by upregulation of BMPR2 and reduced expression of the tumor suppressors CDKN1A (p21) and CDKN2A (p16). These data were confirmed in experimental pulmonary hypertension in vivo. Levels of miR-125a were elevated in lung tissue of hypoxic animals that develop pulmonary hypertension. In contrast, circulating levels of miR-125a were found to be lower in mice with pulmonary hypertension as compared to control mice. Similar findings were observed in a small cohort of patients with precapillary pulmonary hypertension. These translational data emphasize the pathogenetic role of miR-125a in pulmonary vascular remodeling.
authors: Division of Pulmonology, University Hospital Zurich, Zurich CH-8091, Switzerland.
authors: Lars C
authors: LC
authors: Huber
authors: Division of Pulmonology, University Hospital Zurich, Zurich CH-8091, Switzerland.
authors: Silvia
authors: S
authors: Ulrich
authors: Division of Pulmonology, University Hospital Zurich, Zurich CH-8091, Switzerland.
authors: Caroline
authors: C
authors: Leuenberger
authors: Institute of Veterinary Physiology, University of Zurich and Zurich Center for Integrative Human Physiology (ZIHP), Zurich CH-8057, Switzerland.
authors: Max
authors: M
authors: Gassmann
authors: Institute of Veterinary Physiology, University of Zurich and Zurich Center for Integrative Human Physiology (ZIHP), Zurich CH-8057, Switzerland.
authors: Johannes
authors: J
authors: Vogel
authors: Division of Pulmonology, University Hospital Zurich, Zurich CH-8091, Switzerland.
authors: Leonardo Glutz
authors: LG
authors: von Blotzheim
authors: Division of Pulmonology, University Hospital Zurich, Zurich CH-8091, Switzerland.
authors: Rudolf
authors: R
authors: Speich
authors: Division of Pulmonology, University Hospital Zurich, Zurich CH-8091, Switzerland.
authors: Malcolm
authors: M
authors: Kohler
authors: Division of Pulmonology, University Hospital Zurich, Zurich CH-8091, Switzerland Institute of Veterinary Physiology, University of Zurich and Zurich Center for Integrative Human Physiology (ZIHP), Zurich CH-8057, Switzerland Matthias.Brock@usz.ch.
authors: Matthias
authors: M
authors: Brock
mesh_terms: D000818:Animals; D015153:Blotting, Western; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D018844:Cyclin-Dependent Kinases / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D066253:Vascular Remodeling / Q000502:physiology*
chemical_list: C493957:Cdkn1a protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D018844:Cyclin-Dependent Kinases; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: BMPR2; Pulmonary hypertension; anti-miRs; endothelial cell proliferation; microRNAs