Redox-sensitive regulation of the HIF pathway under non-hypoxic conditions in pulmonary artery smooth muscle cells
Redox-sensitive regulation of the HIF pathway under non-hypoxic conditions in pulmonary artery smooth muscle cells
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DOI：
10.1515/bc.2004.019
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发表时间：
2004-03-01
影响因子：
3.7
通讯作者：
Görlach, A
中科院分区：
文献类型：
--
作者：
BelAiba, RS;Djordjevic, T;Görlach, A
肺动脉高压和血管重塑过程与氧化应激、缺氧以及凝血酶和血管内皮生长因子（VEGF）水平升高有关。缺氧诱导转录因子HIF在缺氧条件下调节VEGF的表达。 HIF 通路也可由凝血酶或 CoCl2 激活，可能是通过活性氧 (ROS) 激活。在本研究中，我们研究了氧化还原修饰酶超氧化物歧化酶 (SOD)、谷胱甘肽过氧化物酶 (GPX) 和过氧化氢酶是否影响肺动脉平滑肌细胞 (PASMC) 中的 HIF 水平和 VEGF mRNA 的表达。用凝血酶或CoCl 2 刺激PASMC增加ROS产生并增强HIFα蛋白和VEGF mRNA水平以及HIF依赖性报告基因活性。这些反应受到维生素 C 以及 GPX 和过氧化氢酶过度表达的抑制，而在 SOD 表达细胞中观察到相反的效果。这些发现表明，H2O2 水平降低的抗氧化状态限制了 HIF 通路的激活，而 H2O2 水平升高的促氧化状态则促进了 HIF 通路的激活。因此，将氧化还原平衡转移到更还原的环境，从而限制 VEGF 表达，可能有利于治疗肺动脉高压期间的重塑过程。
Pulmonary hypertension and vascular remodeling processes are associated with oxidative stress, hypoxia and enhanced levels of thrombin and vascular endothelial growth factor (VEGF). The hypoxiainducible transcription factor HIF regulates the expression of VEGF under hypoxia. The HIF pathway is also activated by thrombin or CoCl2, likely via reactive oxygen species (ROS). In this study we investigated whether the redoxmodifying enzymes superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase affect HIF levels and the expression of VEGF mRNA in pulmonary artery smooth muscle cells (PASMC). Stimulation of PASMC with thrombin or CoCl2 increased ROS production and enhanced HIF[alpha] protein and VEGF mRNA levels as well as HIFdependent reporter gene activity. These responses were inhibited by vitamin C and by overexpression of GPX and catalase, whereas the opposite effects were observed in SOD-expressing cells. These findings suggest that an antioxidant state with reduced levels of H2O2 limits the activation of the HIF pathway, whereas a prooxidant state allowing elevated H2O2 levels promotes it. Thus, shifting the redox balance to a more reduced environment, thereby limiting VEGF expression, may be beneficial for treating remodeling processes during pulmonary hypertension.