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Leptin signalling system as a target for pulmonary arterial hypertension therapy

Alice Huertas, Ly Tu, Raphaël Thuillet, Morane Le Hiress, Carole Phan, Nicolas Ricard, Sophie Nadaud, Elie Fadel, Marc Humbert, Christophe Guignabert
European Respiratory Journal 2015 45: 1066-1080; DOI: 10.1183/09031936.00193014
Alice Huertas
1INSERM UMR_S 999, Centre Chirurgical Marie Lannelongue, LabEx LERMIT, Le Plessis-Robinson, France
2Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France
3AP-HP, Service de Pneumologie, DHU Thorax Innovation, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
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Ly Tu
1INSERM UMR_S 999, Centre Chirurgical Marie Lannelongue, LabEx LERMIT, Le Plessis-Robinson, France
2Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France
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Raphaël Thuillet
1INSERM UMR_S 999, Centre Chirurgical Marie Lannelongue, LabEx LERMIT, Le Plessis-Robinson, France
2Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France
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Morane Le Hiress
1INSERM UMR_S 999, Centre Chirurgical Marie Lannelongue, LabEx LERMIT, Le Plessis-Robinson, France
2Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France
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Carole Phan
1INSERM UMR_S 999, Centre Chirurgical Marie Lannelongue, LabEx LERMIT, Le Plessis-Robinson, France
2Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France
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Nicolas Ricard
1INSERM UMR_S 999, Centre Chirurgical Marie Lannelongue, LabEx LERMIT, Le Plessis-Robinson, France
2Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France
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Sophie Nadaud
4INSERM UMR_S 956, Université Pierre and Marie Curie, Paris, France
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Elie Fadel
1INSERM UMR_S 999, Centre Chirurgical Marie Lannelongue, LabEx LERMIT, Le Plessis-Robinson, France
2Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France
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Marc Humbert
1INSERM UMR_S 999, Centre Chirurgical Marie Lannelongue, LabEx LERMIT, Le Plessis-Robinson, France
2Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France
3AP-HP, Service de Pneumologie, DHU Thorax Innovation, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
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Christophe Guignabert
1INSERM UMR_S 999, Centre Chirurgical Marie Lannelongue, LabEx LERMIT, Le Plessis-Robinson, France
2Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France
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Abstract

Excessive proliferation of pulmonary arterial smooth muscle cells (PA-SMCs) and perivascular inflammation lead to pulmonary arterial hypertension (PAH) progression, but they are not specifically targeted by the current therapies. Since leptin (Ob) and its main receptor ObR-b contribute to systemic vascular cell proliferation and inflammation, we questioned whether targeting Ob/ObR-b axis would be an effective antiproliferative and anti-inflammatory strategy against PAH.

In idiopathic PAH (iPAH), using human lung tissues and primary cell cultures (early passages ≤5), we demonstrate that pulmonary endothelial cells (P-ECs) over produce Ob and that PA-SMCs overexpress ObR-b. Furthermore, we obtain evidence that Ob enhances proliferation of human PA-SMCs in vitro and increases right ventricular systolic pressure in Ob-treated mice in the chronic hypoxia-induced pulmonary hypertension (PH) model. Using human cells, we also show that Ob leads to monocyte activation and increases cell adhesion molecule expression levels in P-ECs. We also find that Ob/ObR-b axis contributes to PH susceptibility by using ObR-deficient rats, which display less severe hypoxia-induced PH (pulmonary haemodynamics, arterial muscularisation, PA-SMC proliferation and perivascular inflammation). Importantly, we demonstrate the efficacy of two curative strategies using a soluble Ob neutraliser and dichloroacetate in hypoxia-induced PH.

We demonstrate here that Ob/ObR-b axis may represent anti-proliferative and anti-inflammatory targets in PAH.

Abstract

Targeting Ob/ObR-b axis represents an important tool for anti-proliferative and anti-inflammatory strategies in PH http://ow.ly/I00jh

Footnotes

  • This article has supplementary material available from erj.ersjournals.com

  • Support statement: This research was supported by grants from the French National Institute for Health and Medical Research (INSERM, the French National Agency for Research: grant ANR_12_JSV1_0004_01), from GlaxoSmithKline (PAH grant 2013), and from Pfizer (IIR grant WI182054). Funding information for this article has been deposited with FundRef

  • Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com

  • Received October 17, 2014.
  • Accepted January 19, 2015.
  • Copyright ©ERS 2015
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Leptin signalling system as a target for pulmonary arterial hypertension therapy
Alice Huertas, Ly Tu, Raphaël Thuillet, Morane Le Hiress, Carole Phan, Nicolas Ricard, Sophie Nadaud, Elie Fadel, Marc Humbert, Christophe Guignabert
European Respiratory Journal Apr 2015, 45 (4) 1066-1080; DOI: 10.1183/09031936.00193014

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Leptin signalling system as a target for pulmonary arterial hypertension therapy
Alice Huertas, Ly Tu, Raphaël Thuillet, Morane Le Hiress, Carole Phan, Nicolas Ricard, Sophie Nadaud, Elie Fadel, Marc Humbert, Christophe Guignabert
European Respiratory Journal Apr 2015, 45 (4) 1066-1080; DOI: 10.1183/09031936.00193014
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