Inhibition of MRP4 prevents and reverses pulmonary hypertension in mice

• Published in: The Journal of clinical investigation Vol. 121; no. 7; pp. 2888 - 2897
• Main Authors: Hara, Yannis, Sassi, Yassine, Guibert, Christelle, Gambaryan, Natacha, Dorfmüller, Peter, Eddahibi, Saadia, Lompré, Anne-Marie, Humbert, Marc, Hulot, Jean-Sébastien
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-07-2011
• Subjects: Animals; Biomedical research; Cells, Cultured; Cellular proteins; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Cyclic GMP - metabolism; Cyclic GMP-Dependent Protein Kinases - metabolism; Drug resistance; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - therapeutic use; Familial Primary Pulmonary Hypertension; Heart failure; Human health and pathology; Humans; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - pathology; Hypertension, Pulmonary - prevention & control; Hypoxia; Hypoxia - pathology; Hypoxia - physiopathology; Leukotriene Antagonists - metabolism; Leukotriene Antagonists - therapeutic use; Life Sciences; Localization; Lung - metabolism; Lung - pathology; Lungs; Mice; Mice, Knockout; Multidrug Resistance-Associated Proteins - antagonists & inhibitors; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism; Muscle, Smooth, Vascular - cytology; Physiological aspects; Prevention; Propionates - metabolism; Propionates - therapeutic use; Pulmonary arteries; Pulmonary Artery - cytology; Pulmonary hypertension; Pulmonology and respiratory tract; Quinolines - metabolism; Quinolines - therapeutic use; RNA Interference; Vasoconstriction; Vasodilation; Veins & arteries; France
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci45023

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.