Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension

Nobutoshi Nawa, Hidekazu Ishida, Shinichi Katsuragi, Hiroki Baden, Kunihiko Takahashi, Ryota Higeno, Fumiko Torigoe, Seiko Mihara, Jun Narita, Kohji Miura, Kazufumi Nakamura, Shigetoyo Kogaki, Keiichi Ozono

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)16044
Number of pages1
JournalMolecular Therapy - Methods and Clinical Development
Volume3
DOIs
Publication statusPublished - Mar 16 2016

Fingerprint

Natriuretic Peptides
Peptide Receptors
Pulmonary Hypertension
Cyclic GMP
Sendai virus
Lung
Virus Integration
Blood Pressure
Ligands
Arterioles
Therapeutic Uses
Ventricular Pressure
Genetic Therapy
Pulmonary Artery
Genes
Smooth Muscle Myocytes
Injections
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine

Cite this

Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension. / Nawa, Nobutoshi; Ishida, Hidekazu; Katsuragi, Shinichi; Baden, Hiroki; Takahashi, Kunihiko; Higeno, Ryota; Torigoe, Fumiko; Mihara, Seiko; Narita, Jun; Miura, Kohji; Nakamura, Kazufumi; Kogaki, Shigetoyo; Ozono, Keiichi.

In: Molecular Therapy - Methods and Clinical Development, Vol. 3, 16.03.2016, p. 16044.

Research output: Contribution to journalArticle

Nawa, N, Ishida, H, Katsuragi, S, Baden, H, Takahashi, K, Higeno, R, Torigoe, F, Mihara, S, Narita, J, Miura, K, Nakamura, K, Kogaki, S & Ozono, K 2016, 'Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension', Molecular Therapy - Methods and Clinical Development, vol. 3, pp. 16044. https://doi.org/10.1038/mtm.2016.44
Nawa, Nobutoshi ; Ishida, Hidekazu ; Katsuragi, Shinichi ; Baden, Hiroki ; Takahashi, Kunihiko ; Higeno, Ryota ; Torigoe, Fumiko ; Mihara, Seiko ; Narita, Jun ; Miura, Kohji ; Nakamura, Kazufumi ; Kogaki, Shigetoyo ; Ozono, Keiichi. / Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension. In: Molecular Therapy - Methods and Clinical Development. 2016 ; Vol. 3. pp. 16044.
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