Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension
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 e...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-01-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050117300165 |
| _version_ | 1818140713786802176 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Nobutoshi Nawa |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T10:48:22Z |
| format | Article |
| id | doaj.art-7cff992d35cd444d82737c4f100fd6ae |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-11T10:48:22Z |
| publishDate | 2016-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-7cff992d35cd444d82737c4f100fd6ae2022-12-22T01:10:24ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012016-01-013C10.1038/mtm.2016.44Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertensionNobutoshi Nawa0Hidekazu Ishida1Shinichi Katsuragi2Hiroki Baden3Kunihiko Takahashi4Ryota Higeno5Fumiko Torigoe6Seiko Mihara7Jun Narita8Kohji Miura9Kazufumi Nakamura10Shigetoyo Kogaki11Keiichi Ozono12Department of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, JapanDepartment of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, JapanDepartment of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, JapanDepartment of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, JapanDepartment of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, JapanDepartment of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, JapanDepartment of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, JapanDepartment of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, JapanDepartment of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, JapanDepartment of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, JapanDepartment of Cardiovascular Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, JapanDepartment of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, JapanDepartment of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, JapanWe 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.http://www.sciencedirect.com/science/article/pii/S2329050117300165 |
| spellingShingle | 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 Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension Molecular Therapy: Methods & Clinical Development |
| title | Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension |
| title_full | Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension |
| title_fullStr | Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension |
| title_full_unstemmed | Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension |
| title_short | Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension |
| title_sort | constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension |
| url | http://www.sciencedirect.com/science/article/pii/S2329050117300165 |
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