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Inhibition of MRP4 prevents and reverses pulmonary hypertension in mice
Yannis Hara, … , Marc Humbert, Jean-Sébastien Hulot
Yannis Hara, … , Marc Humbert, Jean-Sébastien Hulot
Published July 1, 2011; First published June 13, 2011
Citation Information: J Clin Invest. 2011;121(7):2888-2897. https://doi.org/10.1172/JCI45023.
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Categories: Research Article Pulmonology

Inhibition of MRP4 prevents and reverses pulmonary hypertension in mice

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Abstract

Multidrug resistance–associated protein 4 (MRP4, also known as Abcc4) regulates intracellular levels of cAMP and cGMP in arterial SMCs. Here, we report our studies of the role of MRP4 in the development and progression of pulmonary arterial hypertension (PAH), a severe vascular disease characterized by chronically elevated pulmonary artery pressure and accompanied by remodeling of the small pulmonary arteries as a prelude to right heart failure and premature death. MRP4 expression was increased in pulmonary arteries from patients with idiopathic PAH as well as in WT mice exposed to hypoxic conditions. Consistent with a pathogenic role for MRP4 in PAH, WT mice exposed to hypoxia for 3 weeks showed reversal of hypoxic pulmonary hypertension (PH) following oral administration of the MRP4 inhibitor MK571, and Mrp4–/– mice were protected from hypoxic PH. Inhibition of MRP4 in vitro was accompanied by increased intracellular cAMP and cGMP levels and PKA and PKG activities, implicating cyclic nucleotide-related signaling pathways in the mechanism underlying the protective effects of MRP4 inhibition. Our data suggest that MRP4 could represent a potential target for therapeutic intervention in PAH.

Authors

Yannis Hara, Yassine Sassi, Christelle Guibert, Natacha Gambaryan, Peter Dorfmüller, Saadia Eddahibi, Anne-Marie Lompré, Marc Humbert, Jean-Sébastien Hulot

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Figure 1

MRP4 expression in control and PAH patients’ lungs.

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MRP4 expression in control and PAH patients’ lungs.
(A) MRP4 localizatio...
(A) MRP4 localization assessed by immunohistochemistry in human pulmonary arteries from control and PAH patients. Arrows indicate the localization of MRP4 proteins found in endothelial cells, SMCs, and pneumocytes. (B) Western blot analysis of MRP4 in lung homogenates from patients showing controls (n = 4) and PAH (n = 4) patients. (C) Quantitative analysis of the results (*P < 0.05). Scale bar: 100 μm.
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