miR-210 promotes IPF fibroblast proliferation in response to hypoxia
Autor: | Mark Peterson, Vidya Bodempudi, Hong Xia, Judy Kahm, Wajahat Khalil, Karen Smith, Craig A. Henke, Polla Hergert, Peter B. Bitterman, Jeremy Herrera |
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Rok vydání: | 2014 |
Předmět: |
Pulmonary and Respiratory Medicine
Pathology medicine.medical_specialty Physiology Biology Cell Line Idiopathic pulmonary fibrosis Physiology (medical) microRNA Basic Helix-Loop-Helix Transcription Factors medicine Humans Gene silencing Hypoxia Fibroblast Lung Cell Proliferation Gene knockdown Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Cell growth Cell Biology Fibroblasts respiratory system Hypoxia (medical) medicine.disease Idiopathic Pulmonary Fibrosis humanities respiratory tract diseases Repressor Proteins MicroRNAs medicine.anatomical_structure Call for Papers Disease Progression Cancer research medicine.symptom |
Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 307:L283-L294 |
ISSN: | 1522-1504 1040-0605 |
DOI: | 10.1152/ajplung.00069.2014 |
Popis: | Idiopathic pulmonary fibrosis (IPF) is characterized by the relentless spread of fibroblasts from scarred alveoli into adjacent alveolar units, resulting in progressive hypoxia and death by asphyxiation. Although hypoxia is a prominent clinical feature of IPF, the role of hypoxia as a driver of the progressive fibrotic nature of the disease has not been explored. Here, we demonstrate that hypoxia robustly stimulates the proliferation of IPF fibroblasts. We found that miR-210 expression markedly increases in IPF fibroblasts in response to hypoxia and that knockdown of miR-210 decreases hypoxia-induced IPF fibroblast proliferation. Silencing hypoxia-inducible factor (HIF)-2α inhibits the hypoxia-mediated increase in miR-210 expression and blocks IPF fibroblast proliferation, indicating that HIF-2α is upstream of miR-210. We demonstrate that the miR-210 downstream target MNT is repressed in hypoxic IPF fibroblasts and that knockdown of miR-210 increases MNT expression. Overexpression of MNT inhibits hypoxia-induced IPF fibroblast proliferation. Together, these data indicate that hypoxia potently stimulates miR-210 expression via HIF-2α, and high miR-210 expression drives fibroblast proliferation by repressing the c-myc inhibitor, MNT. In situ analysis of IPF lung tissue demonstrates miR-210 expression in a similar distribution with HIF-2α and the hypoxic marker carbonic anhydrase-IX in cells within the IPF fibrotic reticulum. Our results raise the possibility that a pathological feed-forward loop exists in the IPF lung, in which hypoxia promotes IPF fibroblast proliferation via stimulation of miR-210 expression, which in turn worsens hypoxia. |
Databáze: | OpenAIRE |
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