Role of copper transport protein antioxidant 1 in angiotensin II-induced hypertension: a key regulator of extracellular superoxide dismutase.
Role of copper transport protein antioxidant 1 in angiotensin II-induced hypertension: a key regulator of extracellular superoxide dismutase.
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DOI：
10.1161/hypertensionaha.111.189571
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发表时间：
2012-08
期刊：
影响因子：
--
通讯作者：
Fukai T
中科院分区：
文献类型：
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作者：
Ozumi K;Sudhahar V;Kim HW;Chen GF;Kohno T;Finney L;Vogt S;McKinney RD;Ushio-Fukai M;Fukai T
细胞外超氧化物歧化酶 (SOD3) 是一种分泌性铜酶，参与保护血管紧张素 II (Ang II) 诱导的高血压。我们之前发现Ang II作为一种反调节机制上调SOD3的表达和活性；然而，根本机制尚不清楚。抗氧化剂-1 (Atox1) 在体外被证明可作为铜依赖性转录因子以及 SOD3 的铜伴侣，但其在体内 Ang II 诱导的高血压中的作用尚不清楚。在这里，我们发现 Ang II 输注会增加野生型小鼠主动脉中 Atox1 的表达以及 SOD3 的表达和活性，而在缺乏 Atox1 的小鼠中，这些表达和活性会受到抑制。因此，与野生型小鼠相比，Atox1−/− 中的Ang II 增加了血管O2•− 的产生，减少了内皮依赖性血管舒张，并增加了肠系膜小动脉的血管收缩。这有助于增强 Atox1−/− 小鼠对 Ang II 的高血压反应。在培养的血管平滑肌细胞中，Ang II 促进 Atox1 易位至细胞核，从而通过与 SOD3 启动子中的 Atox1 响应元件结合来增加 SOD3 转录。此外，Ang II 增加 Atox1 与铜输出蛋白 ATP7A 的结合，从而从 Atox1 获取铜，并增加 ATP7A 易位至质膜，在质膜上与 SOD3 共定位。结果，Ang II 降低了血管铜水平，而 Atox1−/− 小鼠的血管铜水平受到抑制。总之，Atox1 通过增加血管 SOD3 表达和活性来降低细胞外 O2•− 水平，从而预防 Ang II 诱导的内皮功能障碍和抵抗血管过度收缩以及体内高血压。
Extracellular superoxide dismutase (SOD3) is a secretory copper enzyme involved in protecting angiotensin II (Ang II)-induced hypertension. We previously found that Ang II upregulates SOD3 expression and activity as a counter-regulatory mechanism; however, underlying mechanisms are unclear. Antioxidant-1 (Atox1) is shown to act as a copper-dependent transcription factor as well as copper chaperone for SOD3 in vitro, but its role in Ang II-induced hypertension in vivo is unknown. Here we show that Ang II infusion increases Atox1 expression as well as SOD3 expression and activity in aortas of wild-type mice, which are inhibited in mice lacking Atox1. Accordingly, Ang II increases vascular O2•− production, reduces endothelium-dependent vasodilation and increases vasoconstriction in mesenteric arterioles to a greater extent in Atox1−/− than in wild-type mice. This contributes to augmented hypertensive response to Ang II in Atox1−/− mice. In cultured vascular smooth muscle cells, Ang II promotes translocation of Atox1 to the nucleus, thereby increasing SOD3 transcription by binding to Atox1 responsive element in the SOD3 promoter. Furthermore, Ang II increases Atox1 binding to the copper exporter ATP7A which obtains copper from Atox1 as well as translocation of ATP7A to plasma membranes where it colocalizes with SOD3. As its consequence, Ang II decreases vascular copper levels, which is inhibited in Atox1−/− mice. In summary, Atox1 functions to prevent Ang II-induced endothelial dysfunction and hyper-contraction in resistant vessels as well as hypertension in vivo by reducing extracellular O2•− levels via increasing vascular SOD3 expression and activity.