Extracellular Superoxide Dismutase Overexpression Can Reverse the Course of Hypoxia-Induced Pulmonary Hypertension
Extracellular Superoxide Dismutase Overexpression Can Reverse the Course of Hypoxia-Induced Pulmonary Hypertension
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DOI：
10.2119/molmed.2011.00339
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发表时间：
2012-01-01
影响因子：
5.7
通讯作者：
Miller, Edmund J.
中科院分区：
文献类型：
--
作者：
Ahmed, Mohamed N.;Zhang, Yinzhong;Miller, Edmund J.
缺氧导致自由基产生，在肺动脉高压（PH）的病理生理学中具有关键作用。我们推测，细胞外超氧化物歧化酶（EC-SOD）的治疗可以改善缺氧诱导的PH的发展。体外肺微血管内皮细胞研究表明，缺氧24 h后，转染EC-SOD的细胞黄嘌呤氧化酶和活性氧的积累明显少于未转染细胞。为了研究EC-SOD的预防作用，将肺特异性过表达人EC-SOD（hEC-SOD）的成年雄性野生型（WT）和转基因（TG）小鼠暴露于吸入氧分数（FiO（2））为10%的空气中10 d。暴露后，右心室收缩压（RVSP）、右心室质量结果表明，TG小鼠的肺动脉收缩/舒张功能明显优于WT小鼠，且RVSP显著低于WT小鼠（23.9 +/- 1.24 vs 47.2 +/- 3.4）、RV/S + LV（0.287 +/- 0.015 vs 0.335 +/- 0.022）和血管重塑，由PVWT指示（14.324 +/- 1.107 vs 18.885 +/- 1.529）。使用从小鼠分离的肺动脉的功能研究表明，EC-SOD防止缺氧介导的一氧化氮诱导的舒张衰减。通过将WT小鼠暴露于FiO（2）10% 10天来评估治疗潜力。另一半用含编码人EC-SOD的cDNA的质粒转染。剩余的动物用空载体转染。两组均暴露于FiO（2）10%，持续10 d。转染小鼠的RVSP（18.97 +/- 1.12 vs 41.3 +/- 1.5）、RV/S + LV（0.293 +/- 0.012 vs 0.372 +/- 0.014）和PVWT（12.51 +/- 0.72 vs 18.98 +/- 1.24）显著降低。根据这些发现，我们得出结论，EC-SOD的过度表达，防止PH的发展和改善已建立的PH。
Hypoxia leads to free radical production, which has a pivotal role in the pathophysiology of pulmonary hypertension (PH). We hypothesized that treatment with extracellular superoxide dismutase (EC-SOD) could ameliorate the development of PH induced by hypoxia. In vitro studies using pulmonary microvascular endothelial cells showed that cells transfected with EC-SOD had significantly less accumulation of xanthine oxidase and reactive oxygen species than nontransfected cells after hypoxia exposure for 24 h. To study the prophylactic role of EC-SOD, adult male wild-type (WT) and transgenic (TG) mice, with lung-specific overexpression of human EC-SOD (hEC-SOD), were exposed to fraction of inspired oxygen (FiO(2)) 10% for 10 d. After exposure, right ventricular systolic pressure (RVSP), right ventricular mass (RV/S + LV), pulmonary vascular wall thickness (PVWT) and pulmonary artery contraction/relaxation were assessed, TG mice were protected against PH compared with WT mice with significantly lower RVSP (23.9 +/- 1.24 versus 47.2 +/- 3.4), RV/S + LV (0.287 +/- 0.015 versus 0.335 +/- 0.022) and vascular remodeling, indicated by PVWT (14.324 +/- 1.107 versus 18.885 +/- 1.529). Functional studies using pulmonary arteries isolated from mice indicated that EC-SOD prevents hypoxia-mediated attenuation of nitric oxide-induced relaxation. Therapeutic potential was assessed by exposing WT mice to FiO(2) 10% for 10 d. Half of the group was transfected with plasmid containing cDNA encoding human EC-SOD. The remaining animals were transfected with empty vector. Both groups were exposed to FiO(2) 10% for a further 10 d. Transfected mice had significantly reduced RVSP (18.97 +/- 1.12 versus 41.3 +/- 1.5), RV/S + LV (0.293 +/- 0.012 versus 0.372 +/- 0.014) and PVWT (12.51 +/- 0.72 versus 18.98 +/- 1.24). On the basis of these findings, we concluded that overexpression of EC-SOD prevents the development of PH and ameliorates established PH.