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Int. J. Biochem. Cell Biol. · Apr 2015
The hypoxia-induced microRNA-130a controls pulmonary smooth muscle cell proliferation by directly targeting CDKN1A.
- Matthias Brock, Thomas J Haider, Johannes Vogel, Max Gassmann, Rudolf Speich, Michelle Trenkmann, Silvia Ulrich, Malcolm Kohler, and Lars C Huber.
- 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.
- Int. J. Biochem. Cell Biol. 2015 Apr 1; 61: 129-37.
AbstractExcessive 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.Copyright © 2015 Elsevier Ltd. All rights reserved.
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