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Aquaporin 1 controls the functional phenotype of pulmonary smooth muscle cells in hypoxia-induced pulmonary hypertension

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Abstract

Vascular remodelling in hypoxia-induced pulmonary hypertension (PH) is driven by excessive proliferation and migration of endothelial and smooth muscle cells. The expression of aquaporin 1 (AQP1), an integral membrane water channel protein involved in the control of these processes, is tightly regulated by oxygen levels. The role of AQP1 in the pathogenesis of PH, however, has not been directly addressed so far. This study was designed to characterize expression and function of AQP1 in pulmonary vascular cells from human arteries and in the mouse model of hypoxia-induced PH. Exposure of human pulmonary vascular cells to hypoxia significantly induced the expression of AQP1. Similarly, levels of AQP1 were found to be upregulated in lungs of mice with hypoxia-induced PH. The functional role of AQP1 was further tested in human pulmonary artery smooth muscle cells demonstrating that depletion of AQP1 reduced proliferation, the migratory potential, and, conversely, increased apoptosis of these cells. This effect was associated with higher expression of the tumour suppressor gene p53. Using the mouse model of hypoxia-induced PH, application of GapmeR inhibitors targeting AQP1 abated the hypoxia-induced upregulation of AQP1 and, of note, reversed PH by decreasing both right ventricular pressure and hypertrophy back to the levels of control mice. Our data suggest an important functional role of AQP1 in the pathobiology of hypoxia-induced PH. These results offer novel insights in our pathogenetic understanding of the disease and propose AQP1 as potential therapeutic in vivo target.

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Acknowledgements

The authors thank Rudolf Speich for his continuous support of our research, his commitment, and enthusiasm to pulmonary hypertension and many invaluable inputs. We are deeply saddened by his unexpected death. Furthermore, we would like to thank Giovanni Pellegrini from the Institute of Veterinary Physiology of the University of Zurich for his assistance with the animal samples. This work was supported by the Swiss National Science Foundation (SNF Grant 31003A 144212); the Swiss Lung Association (LLS-Nr 2014-09); the Hartmann Müller Foundation; and the Novartis Foundation for medical–biological research (16B086).

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Authors and Affiliations

  1. Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland

    Claudio Schuoler, Thomas J. Haider, Johannes Vogel, Louise Ostergaard & Max Gassmann

  2. Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland

    Claudio Schuoler, Thomas J. Haider, Caroline Leuenberger, Louise Ostergaard, Malcolm Kohler & Max Gassmann

  3. Division of Pulmonology, University Hospital Zurich, University of Zurich, Zurich, Switzerland

    Claudio Schuoler, Caroline Leuenberger, Malcolm Kohler, Lars C. Huber & Matthias Brock

  4. Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria

    Grazyna Kwapiszewska

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  1. Claudio Schuoler
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  2. Thomas J. Haider
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  3. Caroline Leuenberger
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  4. Johannes Vogel
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  7. Malcolm Kohler
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  8. Max Gassmann
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  9. Lars C. Huber
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Corresponding author

Correspondence to Matthias Brock.

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Ethical standards

All animal experiments were approved by the Cantonal Veterinary Office Zurich (Approval Numbers 151/2012 and 212/2014) and performed in accordance with the guidelines from Directive 2010/63/EU of the European Parliament as well as with the ethical standards laid down in the 1964 Declaration of Helsinki.

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The authors declare that they have no conflicts of interest.

Additional information

Claudio Schuoler and Thomas J. Haider share first authorship.

Lars C. Huber and Matthias Brock share senior authorship.

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Schuoler, C., Haider, T.J., Leuenberger, C. et al. Aquaporin 1 controls the functional phenotype of pulmonary smooth muscle cells in hypoxia-induced pulmonary hypertension. Basic Res Cardiol 112, 30 (2017). https://doi.org/10.1007/s00395-017-0620-7

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