title: Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension.
abstract: We recently found a constitutively active mutant of natriuretic peptide receptor 2 (caNPR2; V883M), which synthesizes larger amounts of cyclic guanosine monophosphate (cGMP) intracellularly without any ligand stimulation than existing drugs. The aim of this study was to investigate the therapeutic effects of gene transduction using caNPR2 for pulmonary arterial hypertension (PAH). In vitro gene transduction into human pulmonary arterial smooth muscle cells using Sendai virus (SeV) vectors carrying caNPR2 induced 10,000-fold increases in the synthesis of cGMP without ligand stimulation, and the proliferation of caNPR2-expressing cells was significantly attenuated. The PAH model rats generated by hypoxia and the administration of SU5416 were then treated with SeV vectors through a direct injection into the left pulmonary artery. Right ventricular systolic pressure was significantly decreased 2 weeks after the treatment, while systemic blood pressure remained unchanged. Histological analyses revealed that the medial wall thickness and occlusion rate of pulmonary arterioles were significantly improved in caNPR2-treated lungs. Neither the systemic integration of virus vectors nor side effects were observed. The massive stimulation of cGMP synthesis by gene therapy with caNPR2 was safe and effective in a PAH rat model and, thus, has potential as a novel therapy for patients with severe progressive PAH.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University , Osaka, Japan.
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Nawa
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University , Osaka, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Ishida
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University , Osaka, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Katsuragi
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University , Osaka, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Baden
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University , Osaka, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University , Osaka, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Higeno
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University , Osaka, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Torigoe
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University , Osaka, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Mihara
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University , Osaka, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Narita
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University , Osaka, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Miura
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University , Okayama, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University , Osaka, Japan.
authors.forename: Shigetoyo
authors.initials: S
authors.lastname: Kogaki
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Osaka University , Osaka, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ozono