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J Thorac Cardiovasc Surg 2008;136:142-149
© 2008 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Atrial natriuretic peptide gene transfection with a novel envelope vector system ameliorates pulmonary hypertension in rats

Yoshihide Mitani, MD, PhDa,*, Junko Maruyama, MD, PhDb, Bao Hua Jiang, MD, PhDc, Hirofumi Sawada, MD, PhDa, Hideto Shimpo, MD, PhDd, Kyoko Imanaka–Yoshida, MD, PhDe, Yasufumi Kaneda, MD, PhDf, Yoshihiro Komada, MD, PhDa, Kazuo Maruyama, MD, PhDc

a Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan
b Department of Physiology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
c Department of Anesthesiology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
d Department of Thoracic Cardiovascular Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
e Department of Pathology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
f Department of Molecular Therapy, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

Received for publication July 30, 2007; revisions received October 8, 2007; accepted for publication October 19, 2007.

* Address for reprints: Yoshihide Mitani, MD, PhD, Department of Pediatrics, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie Prefecture, 514-8507, Japan. (Email: ymitani{at}clin.medic.mie-u.ac.jp).

Objectives: 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 β-galactosidase vector, atrial natriuretic peptide vector, or mock vector were investigated for the evaluation of β-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, β-galactosidase. Pulmonary hypertension and transfected gene expression were evaluated.

Results: β-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.

Abbreviations and Acronyms ANP = atrial natriuretic peptide; LV+S = left ventricle plus septum; PA = pulmonary artery; PBS = phosphate-buffered saline; RV = right ventricle; VCAM-1 = vascular cell adhesion molecule 1






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