title: The hypoxia-induced microRNA-130a controls pulmonary smooth muscle cell proliferation by directly targeting CDKN1A.
abstract: Excessive proliferation of human pulmonary artery smooth muscle cells (HPASMC) is one of the major factors that trigger vascular remodeling in hypoxia-induced pulmonary hypertension. Several studies have implicated that hypoxia inhibits the tumor suppressor p21 (CDKN1A). However, the precise mechanism is unknown. The mouse model of hypoxia-induced PH and in vitro experiments were used to assess the impact of microRNAs (miRNAs) on the expression of CDKN1A. In these experiments, the miRNA family miR-130 was identified to regulate the expression of CDKN1A. Transfection of HPASMC with miR-130 decreased the expression of CDKN1A and, in turn, significantly increased smooth muscle proliferation. Conversely, inhibition of miR-130 by anti-miRs and seed blockers increased the expression of CDKN1A. Reporter gene analysis proved a direct miR-130-CDKN1A target interaction. Exposure of HPASMC to hypoxia was found to induce the expression of miR-130 with concomitant decrease of CDKN1A. These findings were confirmed in the mouse model of hypoxia-induced pulmonary hypertension showing that the use of seed blockers against miR-130 restored the expression of CDKN1A. These data suggest that miRNA family miR-130 plays an important role in the repression of CDKN1A by hypoxia. miR-130 enhances hypoxia-induced smooth muscle proliferation and might be involved in the development of right ventricular hypertrophy and vascular remodeling in pulmonary hypertension.
authors: Division of Pulmonology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Institute of Veterinary Physiology, University of Zurich and Zurich Center for Integrative Human Physiology (ZIHP), Zurich, Switzerland. Electronic address: Matthias.Brock@usz.ch.
authors: Matthias
authors: M
authors: Brock
authors: Institute of Veterinary Physiology, University of Zurich and Zurich Center for Integrative Human Physiology (ZIHP), Zurich, Switzerland.
authors: Thomas J
authors: TJ
authors: Haider
authors: Institute of Veterinary Physiology, University of Zurich and Zurich Center for Integrative Human Physiology (ZIHP), Zurich, Switzerland.
authors: Johannes
authors: J
authors: Vogel
authors: Institute of Veterinary Physiology, University of Zurich and Zurich Center for Integrative Human Physiology (ZIHP), Zurich, Switzerland.
authors: Max
authors: M
authors: Gassmann
authors: Division of Pulmonology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors: Rudolf
authors: R
authors: Speich
authors: Center of Experimental Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors: Michelle
authors: M
authors: Trenkmann
authors: Division of Pulmonology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors: Silvia
authors: S
authors: Ulrich
authors: Division of Pulmonology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors: Malcolm
authors: M
authors: Kohler
authors: Division of Pulmonology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors: Lars C
authors: LC
authors: Huber
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism*; D066253:Vascular Remodeling / Q000235:genetics; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C554019:MIRN130 microRNA, human; C582652:MIRN130 microRNA, mouse; D035683:MicroRNAs
keywords: Hypoxia; MicroRNA; Proliferation; Pulmonary hypertension; Vascular remodeling