title: Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension.
abstract: The ATP-binding cassette transporter MRP4 (encoded by ABCC4) regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells. MRP4/ABCC4 deficient mice display a reduction in smooth muscle cells proliferation and a prevention of pulmonary hypertension in response to hypoxia. We aimed to study gene transfer of a MRP4/ABCC4 silencing RNA via intratracheal delivery of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed 35 days later. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >10(11) DRP/animal) as compared to AAV1.
  
  
  METHODS
  The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, ICAN , Paris, France ; INSERM, UMR_S 1166, ICAN , Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Claude
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, PECMV core , Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mougenot
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, ICAN , Paris, France ; INSERM, UMR_S 1166, ICAN , Paris, France.
authors.forename: Julia
authors.initials: J
authors.lastname: Bechaux
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine , New York, New York, USA.
authors.forename: Lahouaria
authors.initials: L
authors.lastname: Hadri
authors.affiliation: Bayer Healthcare, Global Drug Discovery , Wuppertal, Germany.
authors.forename: Damian
authors.initials: D
authors.lastname: Brockschnieder
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, ICAN , Paris, France ; INSERM, UMR_S 1166, ICAN , Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Clergue
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, ICAN , Paris, France ; INSERM, UMR_S 1166, ICAN , Paris, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Atassi
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, ICAN , Paris, France ; INSERM, UMR_S 1166, ICAN , Paris, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lompré
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, ICAN , Paris, France ; INSERM, UMR_S 1166, ICAN , Paris, France ; AP-HP, Hôpital Pitié-Salpêtrière, Department of Pharmacology & Institute of CardioMetabolism and Nutrition , Paris, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot