Selective depletion of vascular EC-SOD augments chronic hypoxic pulmonary hypertension
Selective depletion of vascular EC-SOD augments chronic hypoxic pulmonary hypertension
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DOI：
10.1152/ajplung.00096.2014
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发表时间：
2014-12-01
影响因子：
4.9
通讯作者：
Farrow, Kathryn N.
中科院分区：
文献类型：
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作者：
Nozik-Grayck, Eva;Woods, Crystal;Farrow, Kathryn N.
过量的超氧化物与肺动脉高压（PH）有关。我们以前发现肺过度表达抗氧化剂细胞外超氧化物歧化酶（EC-SOD）减弱PH和肺动脉（PA）重塑。虽然在大多数组织中占总SOD活性的一小部分，但EC-SOD在动脉中含量丰富。我们推测，血管EC-SOD的选择性丧失通过氧化还原敏感的信号通路促进缺氧诱导的PH。EC-SODloxp/loxp x Tg（cre/SMMHC）小鼠（SMC EC-SOD KO）接受他莫昔芬，以条件性消耗平滑肌细胞（SMC）来源的EC-SOD。将小鼠暴露于低压缺氧35天，通过测量右心室收缩压和右心室肥大来评估PH。通过形态学分析和双光子显微镜观察胶原蛋白来评价血管重塑。我们检测了cGMP含量和可溶性鸟苷酸环化酶在肺中的表达和活性，肺磷酸二酯酶5（PDE 5）的表达和活性，以及内皮型一氧化氮合酶和GTP环化水解酶-1（GTPCH-1）的表达，GTP环化水解酶-1（GTPCH-1）是四氢生物蝶呤合成的限速酶。敲除SMC EC-SOD选择性降低PA EC-SOD，而不改变肺总EC-SOD。EC-SOD KO可加重慢性缺氧引起的肺动脉高压和血管重构。SMC EC-SOD的耗竭不影响肺可溶性鸟苷酸环化酶或PDE 5的含量或活性，但减弱了缺氧诱导的cGMP的增加。虽然总eNOS没有改变，但活性eNOS和GTPCH-1仅在SMC EC-SOD KO中随着缺氧而降低。我们的结论是局部损失的PA EC-SOD增强慢性缺氧PH。除了氧化失活的NO，删除EC-SOD似乎降低eNOS活性，进一步损害肺血管功能。
Excess superoxide has been implicated in pulmonary hypertension (PH). We previously found lung overexpression of the antioxidant extracellular superoxide dismutase (EC-SOD) attenuates PH and pulmonary artery (PA) remodeling. Although comprising a small fraction of total SOD activity in most tissues, EC-SOD is abundant in arteries. We hypothesize that the selective loss of vascular EC-SOD promotes hypoxia-induced PH through redox-sensitive signaling pathways. EC-SODloxp/loxp x Tg(cre/SMMHC) mice (SMC EC-SOD KO) received tamoxifen to conditionally deplete smooth muscle cell (SMC)-derived EC-SOD. Mice were exposed to hypobaric hypoxia for 35 days, and PH was assessed by right ventricular systolic pressure measurements and right ventricle hypertrophy. Vascular remodeling was evaluated by morphometric analysis and two-photon microscopy for collagen. We examined cGMP content and soluble guanylate cyclase expression and activity in lung, lung phosphodiesterase 5 (PDE5) expression and activity, and expression of endothelial nitric oxide synthase and GTP cyclohydrolase-1 (GTPCH-1), the rate-limiting enzyme in tetrahydrobiopterin synthesis. Knockout of SMC EC-SOD selectively decreased PA EC-SOD without altering total lung EC-SOD. PH and vascular remodeling induced by chronic hypoxia was augmented in SMC EC-SOD KO. Depletion of SMC EC-SOD did not impact content or activity of lung soluble guanylate cyclase or PDE5, yet it blunted the hypoxia-induced increase in cGMP. Although total eNOS was not altered, active eNOS and GTPCH-1 decreased with hypoxia only in SMC EC-SOD KO. We conclude that the localized loss of PA EC-SOD augments chronic hypoxic PH. In addition to oxidative inactivation of NO, deletion of EC-SOD seems to reduce eNOS activity, further compromising pulmonary vascular function.