Gene transfer of extracellular superoxide dismutase ameliorates pulmonary hypertension in rats
Gene transfer of extracellular superoxide dismutase ameliorates pulmonary hypertension in rats
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DOI：
10.1164/rccm.200702-264oc
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发表时间：
2008-01-15
影响因子：
24.7
通讯作者：
Otsuji, Yutaka
中科院分区：
文献类型：
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作者：
Kamezaki, Fumihiko;Tasaki, Hiromi;Otsuji, Yutaka
依据：肺动脉高压（PH）是一种危及生命的疾病，其特征是血管重塑和血管收缩。有证据表明，氧化应激可能有助于PH的发病和/或发展。目的：在本研究中，我们研究了人细胞外超氧化物歧化酶（EC-SOD）基因转移是否可以改善野百合碱（MCT）诱导的大鼠PH。方法：对注射MCT的大鼠进行溶媒鞘内给药（MCT组）或编码β-半乳糖苷酶的腺病毒（Ad β gal组）或人EC-SOD（AdEC-SOD组）。测量和主要结果：肺内转基因后，EC-SOD在肺组织、支气管肺泡灌洗液和血浆中成功表达。注射MCT后28天，AdEC-SOD组的右心室收缩压和右心室与左心室加室间隔的重量比显著降低（分别为42.50 +/- 1.46 mm Hg和0.453 +/- 0.029）（分别为59.89 ± 1.61 mm Hg和0.636 ± 0.022）或Ad β gal组（分别为61.50 ± 2.61 mm Hg和0.653 ± 0.038）。AdEC-SOD组肺动脉血管重构和平滑肌细胞增殖明显受到抑制。结论：肺组织中EC-SOD过表达可改善MCT诱导的大鼠肺PH。我们认为，EC-SOD可能作为一种抗氧化剂在PH和增加氧化应激可能是重要的MCT诱导的PH的发病机制。
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 beta-galactosidase (Ad beta gal 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 Ad beta gal 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.