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Hypoxia Mediates Mutual Repression between microRNA-27a and PPARγ in the Pulmonary Vasculature
Pulmonary hypertension (PH) is a serious disorder that causes significant morbidity and mortality. The pathogenesis of PH involves complex derangements in multiple pathways including reductions in peroxisome proliferator-activated receptor gamma (PPARγ). Hypoxia, a common PH stimulus, reduces PPARγ...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828382/ https://www.ncbi.nlm.nih.gov/pubmed/24244514 http://dx.doi.org/10.1371/journal.pone.0079503 |
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author | Kang, Bum-Yong Park, Kathy K. Green, David E. Bijli, Kaiser M. Searles, Charles D. Sutliff, Roy L. Hart, C. Michael |
author_facet | Kang, Bum-Yong Park, Kathy K. Green, David E. Bijli, Kaiser M. Searles, Charles D. Sutliff, Roy L. Hart, C. Michael |
author_sort | Kang, Bum-Yong |
collection | PubMed |
description | Pulmonary hypertension (PH) is a serious disorder that causes significant morbidity and mortality. The pathogenesis of PH involves complex derangements in multiple pathways including reductions in peroxisome proliferator-activated receptor gamma (PPARγ). Hypoxia, a common PH stimulus, reduces PPARγ in experimental models. In contrast, activating PPARγ attenuates hypoxia-induced PH and endothelin 1 (ET-1) expression. To further explore mechanisms of hypoxia-induced PH and reductions in PPARγ, we examined the effects of hypoxia on selected microRNA (miRNA or miR) levels that might reduce PPARγ expression leading to increased ET-1 expression and PH. Our results demonstrate that exposure to hypoxia (10% O(2)) for 3-weeks increased levels of miR-27a and ET-1 in the lungs of C57BL/6 mice and reduced PPARγ levels. Hypoxia-induced increases in miR-27a were attenuated in mice treated with the PPARγ ligand, rosiglitazone (RSG, 10 mg/kg/d) by gavage for the final 10 d of exposure. In parallel studies, human pulmonary artery endothelial cells (HPAECs) were exposed to control (21% O(2)) or hypoxic (1% O(2)) conditions for 72 h. Hypoxia increased HPAEC proliferation, miR-27a and ET-1 expression, and reduced PPARγ expression. These alterations were attenuated by treatment with RSG (10 µM) during the last 24 h of hypoxia exposure. Overexpression of miR-27a or PPARγ knockdown increased HPAEC proliferation and ET-1 expression and decreased PPARγ levels, whereas these effects were reversed by miR-27a inhibition. Further, compared to lungs from littermate control mice, miR-27a levels were upregulated in lungs from endothelial-targeted PPARγ knockout (ePPARγ KO) mice. Knockdown of either SP1 or EGR1 was sufficient to significantly attenuate miR-27a expression in HPAECs. Collectively, these studies provide novel evidence that miR-27a and PPARγ mediate mutually repressive actions in hypoxic pulmonary vasculature and that targeting PPARγ may represent a novel therapeutic approach in PH to attenuate proliferative mediators that stimulate proliferation of pulmonary vascular cells. |
format | Online Article Text |
id | pubmed-3828382 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-38283822013-11-16 Hypoxia Mediates Mutual Repression between microRNA-27a and PPARγ in the Pulmonary Vasculature Kang, Bum-Yong Park, Kathy K. Green, David E. Bijli, Kaiser M. Searles, Charles D. Sutliff, Roy L. Hart, C. Michael PLoS One Research Article Pulmonary hypertension (PH) is a serious disorder that causes significant morbidity and mortality. The pathogenesis of PH involves complex derangements in multiple pathways including reductions in peroxisome proliferator-activated receptor gamma (PPARγ). Hypoxia, a common PH stimulus, reduces PPARγ in experimental models. In contrast, activating PPARγ attenuates hypoxia-induced PH and endothelin 1 (ET-1) expression. To further explore mechanisms of hypoxia-induced PH and reductions in PPARγ, we examined the effects of hypoxia on selected microRNA (miRNA or miR) levels that might reduce PPARγ expression leading to increased ET-1 expression and PH. Our results demonstrate that exposure to hypoxia (10% O(2)) for 3-weeks increased levels of miR-27a and ET-1 in the lungs of C57BL/6 mice and reduced PPARγ levels. Hypoxia-induced increases in miR-27a were attenuated in mice treated with the PPARγ ligand, rosiglitazone (RSG, 10 mg/kg/d) by gavage for the final 10 d of exposure. In parallel studies, human pulmonary artery endothelial cells (HPAECs) were exposed to control (21% O(2)) or hypoxic (1% O(2)) conditions for 72 h. Hypoxia increased HPAEC proliferation, miR-27a and ET-1 expression, and reduced PPARγ expression. These alterations were attenuated by treatment with RSG (10 µM) during the last 24 h of hypoxia exposure. Overexpression of miR-27a or PPARγ knockdown increased HPAEC proliferation and ET-1 expression and decreased PPARγ levels, whereas these effects were reversed by miR-27a inhibition. Further, compared to lungs from littermate control mice, miR-27a levels were upregulated in lungs from endothelial-targeted PPARγ knockout (ePPARγ KO) mice. Knockdown of either SP1 or EGR1 was sufficient to significantly attenuate miR-27a expression in HPAECs. Collectively, these studies provide novel evidence that miR-27a and PPARγ mediate mutually repressive actions in hypoxic pulmonary vasculature and that targeting PPARγ may represent a novel therapeutic approach in PH to attenuate proliferative mediators that stimulate proliferation of pulmonary vascular cells. Public Library of Science 2013-11-14 /pmc/articles/PMC3828382/ /pubmed/24244514 http://dx.doi.org/10.1371/journal.pone.0079503 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article Kang, Bum-Yong Park, Kathy K. Green, David E. Bijli, Kaiser M. Searles, Charles D. Sutliff, Roy L. Hart, C. Michael Hypoxia Mediates Mutual Repression between microRNA-27a and PPARγ in the Pulmonary Vasculature |
title | Hypoxia Mediates Mutual Repression between microRNA-27a and PPARγ in the Pulmonary Vasculature |
title_full | Hypoxia Mediates Mutual Repression between microRNA-27a and PPARγ in the Pulmonary Vasculature |
title_fullStr | Hypoxia Mediates Mutual Repression between microRNA-27a and PPARγ in the Pulmonary Vasculature |
title_full_unstemmed | Hypoxia Mediates Mutual Repression between microRNA-27a and PPARγ in the Pulmonary Vasculature |
title_short | Hypoxia Mediates Mutual Repression between microRNA-27a and PPARγ in the Pulmonary Vasculature |
title_sort | hypoxia mediates mutual repression between microrna-27a and pparγ in the pulmonary vasculature |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828382/ https://www.ncbi.nlm.nih.gov/pubmed/24244514 http://dx.doi.org/10.1371/journal.pone.0079503 |
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