Abstract 16716: Intravascular Injection of Sendai Virus Vector Carrying Continuously cGMP Producing Mutant of Type B Natriuretic Peptide Receptor Can Ameliorate Pulmonary Arterial Hypertension
Introduction: Type B natriuretic peptide receptor (NPR-B) is one of the transmembrane guanylyl cyclases and synthesizes cGMP on C-type natriuretic peptide binding. We have found a novel constitutively active mutation in the NPR-B gene in a family case showing overgrowth and bone anomalies. Previously, we constructed adenovirus vectors carrying this mutant NPR-B and administered to Sugen PAH rats intratracheally to investigate its therapeutic effect. However, the use of adenovirus vectors actually caused inflammatory host response in the lung.
Objective: Sendai virus vector (SeV) is well known for its high transduction efficiency as well as the low toxicity. Recently, the results of a Phase I/IIa clinical study of SeV in human peripheral arterial disease have been reported. The objective of this study was to investigate the therapeutic effect of SeV carrying constitutively active mutant of NPR-B for PAH in rats.
Methods and Results: We constructed SeV carrying wild-type (WT), and mutant (Mut) NPR-B. Control SeV carrying Azami-Green was purchased from MBL (Medical & Biological laboratories, Nagoya, Japan). The overexpression of the mutant in human pulmonary artery smooth muscle cells by SeV induced significant increase in cGMP levels (control, 0.193±0.115 pmol/mL; WT-NPR-B, 38.3±29.6 pmol/mL; Mut-NPR-B, 2460±577 pmol/mL; n=3; p<0.01), and suppressed proliferation as assessed by 5-ethynyl-2′-deoxyuridine (EdU) incorporation (EdU positive ratio: control, 0.18±0.017; WT, 0.12±0.023; Mut, 0.085±0.010; n=6; P < 0.05).
In Sugen PAH rats, intravascular administration of SeV carrying Mut-NPR-B significantly decreased right ventricular systolic pressure (Control, 61.4±8.4 mmHg; WT, 61.5±5.4 mmHg; Mut, 46.9±4.9mmHg; n=6; p<0.01) and the ratio of right ventricular/left ventricular pressure (Control, 0.67±0.05; WT, 0.70±0.03; Mut, 0.53±0.09; n=6; p<0.01). Furthermore, the proportion of occluded arteries was lower in Mut transduced rats than in control or WT transduced rats histologically.
Conclusions: The CNP/NPR-B signaling pathway is an additional therapeutic target for the treatment of PAH. The enhancement of CNP/NPR-B pathway could ameliorate both intimal and medial remodeling of pulmonary artery in PAH.
Author Disclosures: N. Nawa: None. H. Ishida: None. S. Katuragi: None. H. Baden: None. K. Takahashi: None. S. Kogaki: None. R. Higeno: None. F. Torigoe: None. S. Mihara: None. J. Narita: None. K. Miura: None. K. Ozono: None.
- © 2015 by American Heart Association, Inc.