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Gene Transfer of Extracellular Superoxide Dismutase Ameliorates Pulmonary Hypertension in Rats

¹ Second Department of Internal Medicine, and Departments of ² Pharmacology and ³ Pathology, School of Medicine, University of Occupational and Environmental Health, Kitakyusyu, Japan; and ⁴ Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan

Correspondence and requests for reprints should be addressed to Hiromi Tasaki, M.D., Ph.D., Second Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku 807-8555, Kitakyushu, Japan. E-mail: h-tasaki{at}med.uoeh-u.ac.jp

Rationale: Pulmonary hypertension (PH) is a life-threatening disease, characterized by vascular remodeling and vasoconstriction. Evidence suggests that oxidative stress may contribute to the pathogenesis and/or development of PH.

Objectives: In the present study, we examined whether intratracheal gene transfer of human extracellular superoxide dismutase (EC-SOD) could ameliorate monocrotaline (MCT)–induced PH in rats.

Methods: MCT-injected rats were intratracheally administered vehicle (MCT group) or an adenovirus encoding β-galactosidase (Adβgal group) or human EC-SOD (AdEC-SOD group).

Measurements and Main Results: After intratracheal gene transfer, EC-SOD was successfully expressed in lung tissue, bronchoalveolar lavage fluid, and plasma. Twenty-eight days after MCT injection, right ventricular systolic pressure and the weight ratio of the right ventricle to the left ventricle plus septum were significantly lower in the AdEC-SOD group (42.50 ± 1.46 mm Hg and 0.453 ± 0.029, respectively) than in the MCT group (59.89 ± 1.61 mm Hg and 0.636 ± 0.022, respectively) or the Adβgal group (61.50 ± 2.61 mm Hg and 0.653 ± 0.038, respectively). Moreover, vascular remodeling and proliferation of vascular smooth muscle cells in pulmonary arteries were markedly suppressed in the AdEC-SOD group. Importantly, 8-isoprostane in lung tissue was also significantly reduced in the AdEC-SOD group.

Conclusions: EC-SOD overexpression to the lung ameliorated MCT-induced PH in rats. We suggest that EC-SOD may act as an antioxidant in PH and that increased oxidative stress may be important in the pathogenesis of MCT-induced PH.

Key Words: monocrotaline • oxidative stress • intratracheal gene transfer • epithelial cell

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Extracellular superoxide dismutase (EC-SOD) may be involved in the pathogenesis of various lung diseases, but the role of EC-SOD in pulmonary hypertension remains unclear. What This Study Adds to the Field EC-SOD may act as an antioxidant in pulmonary hypertension. Increased oxidative stress may play an important role in the pathogenesis of monocrotaline-induced pulmonary hypertension.

 

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