Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension
نویسندگان
چکیده
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.
منابع مشابه
Adenoassociated virus-mediated prostacyclin synthase expression prevents pulmonary arterial hypertension in rats.
Prostacyclin synthase (PGIS) is the final committed enzyme in the metabolic pathway of prostacyclin production. The therapeutic option of intravenous prostacyclin infusion in patients with pulmonary arterial hypertension is limited by the short half-life of the drug and life-threatening catheter-related complications. To develop a better delivery system for prostacyclin, we examined the feasibi...
متن کاملInhibition of MRP4 prevents and reverses pulmonary hypertension in mice.
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 pul...
متن کاملAAV delivery of tumor necrosis factor-α short hairpin RNA attenuates cold-induced pulmonary hypertension and pulmonary arterial remodeling.
Cold temperatures are associated with increased mortality and morbidity of cardiovascular and pulmonary disease. Cold exposure causes lung inflammation, pulmonary hypertension (PH), and right ventricle hypertrophy, but there is no effective therapy because of unknown mechanism. Here, we investigated whether RNA interference silencing of tumor necrosis factor (TNF)-α decreases cold-induced macro...
متن کاملChronic intermittent hypobaric hypoxia attenuates monocrotaline-induced pulmonary arterial hypertension via modulating inflammation and suppressing NF-κB /p38 pathway
Objective(s): Inflammation is involved in various forms of pulmonary arterial hypertension (PAH). Although the pathophysiology of PAH remains uncertain, NF-κB and p38 mitogen-activated protein kinase (p38 MAPK) has been reportedto be associated with many inflammatory mediators of PAH. This study aimed to evaluate the effect of chronic intermittent hypobaric hypoxia (CIHH) on pulmonary inflammat...
متن کاملPulmonary Hypertension Nanoparticle-Mediated Delivery of Nuclear Factor B Decoy Into Lungs Ameliorates Monocrotaline-Induced Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is an intractable disease of the small pulmonary artery that involves multiple inflammatory factors. We hypothesized that a redox-sensitive transcription factor, nuclear factor B (NFB), which regulates important inflammatory cytokines, plays a pivotal role in PAH. We investigated the activity of NFB in explanted lungs from patients with PAH and in a rat mod...
متن کامل