Atrial natriuretic peptide gene transfection with a novel envelope vector system ameliorates pulmonary hypertension in rats.
OBJECTIVE
A novel hemagglutinating virus of Japan (HVJ, a murine parainfluenza virus) envelope vector system, in which DNA is incorporated into an inactivated viral particle deprived of its genome, was recently developed as a ready-to-use vector for gene therapy. We therefore investigated whether intratracheal gene transfer using this vector can induce transgene expression in the lung and whether atrial natriuretic peptide gene transfer ameliorates pulmonary hypertension in rats.


METHODS
Rats transfected intratracheally with beta-galactosidase vector, atrial natriuretic peptide vector, or mock vector were investigated for the evaluation of beta-galactosidase expression, atrial natriuretic peptide mRNA expression, and inflammatory cell infiltration. Rats were divided into 5 treatment groups (n = 73): normoxic rats treated intratracheally with mock vector or atrial natriuretic peptide gene and chronic hypoxic rats treated similarly with mock vector, atrial natriuretic peptide, or a reporter gene, beta-galactosidase. Pulmonary hypertension and transfected gene expression were evaluated.


RESULTS
Beta-galactosidase gene transfer induced its intense enzymatic activity in bronchial and alveolar epithelial cells but not in other organs in normoxic rats. Transfected lungs were not associated with inflammatory cell infiltration. Atrial natriuretic peptide gene transfection inhibited pulmonary hypertension, which is associated with its mRNA expression in the lungs. Indices of right ventricular hypertrophy and pulmonary vascular diseases induced by chronic hypoxia were significantly but incompletely ameliorated.


CONCLUSIONS
HVJ-envelope vector is an efficient, relatively safe, and ready-to-use gene delivery system for pulmonary vascular diseases. Atrial natriuretic peptide gene transfer to lungs by using this vector could be a promising therapeutic approach against pulmonary hypertension.
Mitani
Yoshihide
Y
Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan. ymitani@clin.medic.mie-u.ac.jp)
Maruyama
Junko
J
Jiang
Bao Hua
BH
Sawada
Hirofumi
H
Shimpo
Hideto
H
Imanaka-Yoshida
Kyoko
K
Kaneda
Yasufumi
Y
Komada
Yoshihiro
Y
Maruyama
Kazuo
K
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000235:genetics*; D004195:Disease Models, Animal; D004727:Endothelium / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D008168:Lung / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000235:genetics; D001616:beta-Galactosidase / Q000235:genetics
D019010:Vascular Cell Adhesion Molecule-1; D014759:Viral Envelope Proteins; D009320:Atrial Natriuretic Factor; D001616:beta-Galactosidase