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Int. J. Mol. Sci. 2018, 19(8), 2372; https://doi.org/10.3390/ijms19082372

Prostanoid EP2 Receptors Are Up-Regulated in Human Pulmonary Arterial Hypertension: A Key Anti-Proliferative Target for Treprostinil in Smooth Muscle Cells

1
Institute of Cardiovascular Science, University College London, London WC1E 6JF, UK
2
Infectious Diseases and Immunity, University College London, London WC1N 1EH, UK
3
INSERM U1148, CHU X. Bichat, Paris Cedex 18, 75877 Paris, France
4
Respiratory Centre for Inflammation and Tissue Repair, University College London, London WC1E 6JF, UK
5
Paediatric Cardiology, Great Ormond Street Hospital, London WC1N 3JH, UK
6
United Therapeutics Corporation, Research Triangle Park, NC 27709, USA
7
William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK
*
Author to whom correspondence should be addressed.
Received: 18 July 2018 / Revised: 8 August 2018 / Accepted: 9 August 2018 / Published: 12 August 2018
(This article belongs to the Special Issue Molecular Research on Pulmonary Hypertension)
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Abstract

Prostacyclins are extensively used to treat pulmonary arterial hypertension (PAH), a life-threatening disease involving the progressive thickening of small pulmonary arteries. Although these agents are considered to act therapeutically via the prostanoid IP receptor, treprostinil is the only prostacyclin mimetic that potently binds to the prostanoid EP2 receptor, the role of which is unknown in PAH. We hypothesised that EP2 receptors contribute to the anti-proliferative effects of treprostinil in human pulmonary arterial smooth muscle cells (PASMCs), contrasting with selexipag, a non-prostanoid selective IP agonist. Human PASMCs from PAH patients were used to assess prostanoid receptor expression, cell proliferation, and cyclic adenosine monophosphate (cAMP) levels following the addition of agonists, antagonists or EP2 receptor small interfering RNAs (siRNAs). Immunohistochemical staining was performed in lung sections from control and PAH patients. We demonstrate using selective IP (RO1138452) and EP2 (PF-04418948) antagonists that the anti-proliferative actions of treprostinil depend largely on EP2 receptors rather than IP receptors, unlike MRE-269 (selexipag-active metabolite). Likewise, EP2 receptor knockdown selectively reduced the functional responses to treprostinil but not MRE-269. Furthermore, EP2 receptor levels were enhanced in human PASMCs and in lung sections from PAH patients compared to controls. Thus, EP2 receptors represent a novel therapeutic target for treprostinil, highlighting key pharmacological differences between prostacyclin mimetics used in PAH. View Full-Text
Keywords: prostacyclin; prostaglandin; EP2 receptor; human; treprostinil; selexipag; pulmonary arterial smooth muscle cell proliferation; IP receptor agonists; pulmonary hypertension prostacyclin; prostaglandin; EP2 receptor; human; treprostinil; selexipag; pulmonary arterial smooth muscle cell proliferation; IP receptor agonists; pulmonary hypertension
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Patel, J.A.; Shen, L.; Hall, S.M.; Benyahia, C.; Norel, X.; McAnulty, R.J.; Moledina, S.; Silverstein, A.M.; Whittle, B.J.; Clapp, L.H. Prostanoid EP2 Receptors Are Up-Regulated in Human Pulmonary Arterial Hypertension: A Key Anti-Proliferative Target for Treprostinil in Smooth Muscle Cells. Int. J. Mol. Sci. 2018, 19, 2372.

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