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Inhibition of HIF/Ob/ObR-b axis reverses experimental pulmonary hypertension - 04/04/15

Doi : 10.1016/j.rmr.2015.02.062 
A. Huertas 1, 2, 3, , L. Tu 1, 2, 3, R. Thuillet 1, 2, 3, M. Le Hiress 1, 2, 3, C. Phan 1, 2, 3, M. Humbert 1, 2, 3, C. Guignabert 1, 2, 3
1 Inserm UMR_S 999, Hôpital Marie-Lannelongue, Le Plessis-Robinson, France 
2 Université Paris-Sud, Orsay, France 
3 AP–HP, Centre de référence de l’hypertension pulmonaire sévère, DHU TORINO, Hôpital Bicêtre, le Kremlin-Bicêtre, France 

Corresponding author.

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Résumé

Introduction

Excessive pulmonary smooth muscle cell (P-SMC) proliferation and perivascular infiltration lead to irreversible remodeling in pulmonary arterial hypertension (PAH), contributing to the disease severity. However, these mechanisms are not specifically targeted by the current PAH therapies. Since leptin (Ob), a HIF-dependent gene, and its receptor ObR-b contribute to systemic vascular remodeling, we questioned whether targeting HIF/Ob/ObR-b axis would be an effective anti-proliferative and anti-inflammatory strategy against PAH.

Methods

We used control and PAH human lung tissues and human primary cultures (early passages5) of pulmonary endothelial cells (P-ECs) and P-SMCs. Experimental pulmonary hypertension (PH) was induced in rodents by exposing them to chronic hypoxia (3 weeks, FiO2=10%). We used respectively ObR-deficient rats (ObR-/−) and their wild type littermates, an inductive treatment with recombinant Ob (3μg/g by daily IP injections) and 2 different curative strategies, a soluble Ob neutralizer (ObR: Fc, 100μg/day by IP injections) and an indirect HIF/Ob inhibitor, dichloroacetate (DCA, 1g/L in drinking water).

Results

By using control and human lung tissues and human primary cultures, we demonstrate that in idiopathic PAH:

– P-ECs overproduce Ob, in a HIF-dependent manner, and P-SMCs overexpress ObR-b, as compared to controls;

– P-SMCs proliferate more in response to exogenous Ob than controls;

– increased P-EC-derived Ob leads to an excessive P-SMC proliferation;

– Ob drives perivascular inflammation by activating monocytes and macrophages and by inducing cell adhesion molecule expression in P-ECs.

Consistently, we show that Ob administration can worsen PH severity in mice. We also demonstrate that Ob/ObR-b axis contributes to PH susceptibility, using ObR-/− rats, which displayed less severe hypoxia-induced PH, as assessed by pulmonary hemodynamics, arterial muscularization, P-SMC proliferation and perivascular inflammation. Importantly, we demonstrate the efficacy of 2 curative strategies targeting Ob/ObR-b axis in experimental PH: ObR:Fc and DCA.

Conclusion

We demonstrate here, for the first time, that targeting HIF/Ob/ObR-b axis represents an important therapeutical tool to develop anti-proliferative and anti-inflammatory strategies in experimental PH development and progression.

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Keyword : Circulation


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© 2015  Publié par Elsevier Masson SAS.
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Vol 32 - N° 3

P. 329 - mars 2015 Retour au numéro
Article précédent Article précédent
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