Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension.

Abstract

UNLABELLED:

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.

CONTROL:

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: Caroline Claude, Nathalie Mougenot, Julia Bechaux, Lahouaria Hadri, Damian Brockschnieder, Michel Clergue, Fabrice Atassi, Anne-Marie Lompré, Jean-Sébastien Hulot
• Journal: Molecular therapy. Methods & clinical development (Mol Ther Methods Clin Dev) Vol. 2 Pg. 14065 ( 2015) ISSN: 2329-0501 [Print] United States
• PMID: 26052533 (Publication Type: Journal Article)