Gene transfer of extracellular superoxide dismutase ameliorates pulmonary hypertension in rats.
BACKGROUND
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.


OBJECTIVE
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 beta-galactosidase (Adbetagal group) or human EC-SOD (AdEC-SOD group).


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 Adbetagal 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.
Kamezaki
Fumihiko
F
Second Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku 807-8555, Kitakyushu, Japan. h-tasaki@med.uoeh-u.ac.jp
Tasaki
Hiromi
H
Yamashita
Kazuhito
K
Tsutsui
Masato
M
Koide
Shinichiro
S
Nakata
Sei
S
Tanimoto
Akihide
A
Okazaki
Masahiro
M
Sasaguri
Yasuyuki
Y
Adachi
Tetsuo
T
Otsuji
Yutaka
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001794:Blood Pressure; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004195:Disease Models, Animal; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006339:Heart Rate; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008168:Lung / Q000378:metabolism; D016686:Monocrotaline; D011651:Pulmonary Artery / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D001616:beta-Galactosidase / Q000378:metabolism
D016686:Monocrotaline; D013482:Superoxide Dismutase; D001616:beta-Galactosidase