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Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension
- Source :
- Molecular Therapy: Methods & Clinical Development, Vol 3, Iss C (2016), Molecular Therapy. Methods & Clinical Development
- Publication Year :
- 2016
- Publisher :
- Elsevier, 2016.
-
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.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
lcsh:QH426-470
Genetic enhancement
Stimulation
030204 cardiovascular system & hematology
Article
03 medical and health sciences
Transduction (genetics)
chemistry.chemical_compound
0302 clinical medicine
Internal medicine
Genetics
medicine
lcsh:QH573-671
Molecular Biology
Cyclic guanosine monophosphate
biology
business.industry
lcsh:Cytology
Left pulmonary artery
biology.organism_classification
In vitro
Sendai virus
lcsh:Genetics
030104 developmental biology
Endocrinology
chemistry
Ventricular pressure
Molecular Medicine
business
Subjects
Details
- Language :
- English
- ISSN :
- 23290501
- Volume :
- 3
- Database :
- OpenAIRE
- Journal :
- Molecular Therapy: Methods & Clinical Development
- Accession number :
- edsair.doi.dedup.....5e5cc292ad49f7e727a9400619690c95