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Author Notes:

Correspondence: E-mail: michael.hart3@va.gov

Conceived and designed the experiments: BYK CMH.

Performed the experiments: BYK KKP.

Analyzed the data: BYK.

Contributed reagents/materials/analysis tools: BYK KKP.

Wrote the paper: BYK DEG KMB CDS RLS CMH.

The authors greatly acknowledge the expert technical assistance of Jennifer Kleinhenz, Jing Ma, and Tammy Murphy.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors have declared that no competing interests exist.


Research Funding:

This study was supported by funding from a Veterans Affairs Merit Review Award (1I01BX001910 to CMH), from NIH grants DK 074518 and HL102167 (to CMH and RLS), and from an American Heart Association National Scientist Development Grant (13SDG14150004 to BYK).


  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • LUNG
  • MicroRNAs
  • Medical hypoxia
  • Small interfering RNAs
  • Transfection
  • Pathogenesis
  • Hypoxia
  • Messenger RNA
  • Mouse models

Hypoxia Mediates Mutual Repression between microRNA-27a and PPAR gamma in the Pulmonary Vasculature


Journal Title:



Volume 8, Number 11


, Pages e79503-e79503

Type of Work:

Article | Final Publisher PDF


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 E GR1 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.

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This is an Open Access work distributed under the terms of the Creative Commons Universal : Public Domain Dedication License (http://creativecommons.org/publicdomain/zero/1.0/).

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