Angiotensin-(1-7) counteracts angiotensin II-induced dysfunction in cerebral endothelial cells via modulating Nox2/ROS and PI3K/NO pathways.
Angiotensin-(1-7) counteracts angiotensin II-induced dysfunction in cerebral endothelial cells via modulating Nox2/ROS and PI3K/NO pathways.
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血管紧张素-(1-7) 通过调节 Nox2/ROS 和 PI3K/NO 途径抵消血管紧张素 II 诱导的脑内皮细胞功能障碍。
DOI：
10.1016/j.yexcr.2015.06.010
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发表时间：
2015-08-01
影响因子：
3.7
通讯作者：
Bihl JC
中科院分区：
文献类型：
--
作者：
Xiao X;Zhang C;Ma X;Miao H;Wang J;Liu L;Chen S;Zeng R;Chen Y;Bihl JC
血管紧张素 (Ang) II 是肾素-血管紧张素系统的主要效应物，与血管疾病的发病机制有关。 Ang-(1-7) 与 G 蛋白偶联 Mas 受体 (MasR) 结合，可以发挥血管保护作用。我们研究了 Ang-(1-7) 对 Ang II 诱导的人脑微血管内皮细胞 (HbmEC) 功能障碍和氧化应激的影响和潜在机制。测量了 HbmEC 中的促凋亡活性、活性氧 (ROS) 和一氧化氮 (NO) 的产生。通过蛋白质印迹法检测烟酰胺腺嘌呤二核苷酸磷酸氧化酶 2 (Nox2)、丝氨酸/苏氨酸激酶 (Akt)、内皮一氧化氮合酶 (eNOS) 及其磷酸化形式（p-Akt 和 p-eNOS）的蛋白表达。 MasR 拮抗剂和磷脂酰肌醇 3 激酶 (PI3K) 抑制剂用于受体/通路验证。我们发现 Ang-(1-7) 抑制 Ang II 诱导的 HbmEC 中促凋亡活性、ROS 过量产生和 NO 减少，而 MasR 拮抗剂可消除这些作用。此外，Ang-(1-7)下调HbmECs中Nox2的表达，上调p-Akt/Akt及其下游p-eNOS/eNOS的比值。暴露于 PI3K 抑制剂可部分消除 Ang-(1-7) 介导的 HbmEC 保护作用。我们的数据表明，Ang-(1-7)/MasR 轴通过抑制 Nox2/ROS 和激活 PI3K/NO 途径，保护 HbmEC 免受 Ang II 诱导的功能障碍和氧化应激的影响。
Angiotensin (Ang) II, the main effector of the renin-angiotensin system, has been implicated in the pathogenesis of vascular diseases. Ang-(1-7) binds to the G protein-coupled Mas receptor (MasR) and can exert vasoprotective effects. We investigated the effects and underlying mechanisms of Ang-(1-7) on Ang II-induced dysfunction and oxidative stress in human brain microvascular endothelial cells (HbmECs). The pro-apoptotic activity, reactive oxygen species (ROS) and nitric oxide (NO) productions in HbmECs were measured. The protein expressions of nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2), serine/threonine kinase (Akt), endothelial nitric oxide synthase (eNOS) and their phosphorylated forms (p-Akt and p-eNOS) were examined by western blot. MasR antagonist and phosphatidylinositol-3-kinase (PI3K) inhibitor were used for receptor/pathway verification. We found that Ang-(1-7) suppressed Ang II-induced pro-apoptotic activity, ROS over-production and NO reduction in HbmECs, which were abolished by MasR antagonist. In addition, Ang-(1-7) down-regulated the expression of Nox2, and up-regulated the ratios of p-Akt/Akt and its downstream p-eNOS/eNOS in HbmECs. Exposure to PI3K inhibitor partially abrogated Ang-(1-7)-mediated protective effects in HbmECs. Our data suggests that Ang-(1-7)/MasR axis protects HbmECs from Ang II-induced dysfunction and oxidative stress via inhibition of Nox2/ROS and activation of PI3K/NO pathways.