title: Inhibition of MRP4 prevents and reverses pulmonary hypertension in mice.
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.affiliation: UPMC Univ Paris 06, UMRS 956, Paris, France.
authors.forename: Yannis
authors.initials: Y
authors.lastname: Hara
authors.forename: Yassine
authors.initials: Y
authors.lastname: Sassi
authors.forename: Christelle
authors.initials: C
authors.lastname: Guibert
authors.forename: Natacha
authors.initials: N
authors.lastname: Gambaryan
authors.forename: Peter
authors.initials: P
authors.lastname: Dorfmüller
authors.forename: Saadia
authors.initials: S
authors.lastname: Eddahibi
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lompré
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology; D020024:Leukotriene Antagonists / Q000378:metabolism / Q000627:therapeutic use; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D011422:Propionates / Q000378:metabolism / Q000627:therapeutic use*; D011651:Pulmonary Artery / Q000166:cytology; D011804:Quinolines / Q000378:metabolism / Q000627:therapeutic use*; D034622:RNA Interference; D014661:Vasoconstriction; D014664:Vasodilation
chemical_list: D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D006152:Cyclic GMP; D017869:Cyclic GMP-Dependent Protein Kinases; D004791:Enzyme Inhibitors; D020024:Leukotriene Antagonists; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates; D011804:Quinolines; C489540:Abcc4 protein, mouse; C059141:verlukast