Supplemental Digital Content is available in the text. We investigated the mechanism by which ACE2 (angiotensin-converting enzyme 2) overexpression alters neurohumoral outflow and central oxidative stress. Nrf2 (nuclear factor [erythroid-derived 2]-like 2) is a master antioxidant transcription factor that regulates cytoprotective and antioxidant genes. We hypothesized that upregulation of central ACE2 inhibits the pressor response to Ang II (angiotensin II) by reducing reactive oxygen species through a Nrf2/antioxidant enzyme–mediated mechanism in the rostral ventrolateral medulla. Synapsin human Angiotensin Converting Enzyme 2 positive (SynhACE2+/+) mice and their littermate controls synhACE2−/− were used to evaluate the consequence of intracerebroventricular infusion of Ang II. In control mice, Ang II infusion evoked a significant increase in blood pressure and norepinephrine excretion, along with polydipsia and polyuria. The pressor effect of central Ang II was completely blocked in synhACE2+/+ mice. Polydipsia, norepinephrine excretion, and markers of oxidative stress in response to central Ang II were also reduced in synhACE2+/+ mice. The MasR (Mas receptor) agonist Ang 1–7 and blocker A779 had no effects on blood pressure. synhACE2+/+ mice showed enhanced expression of Nrf2 in the rostral ventrolateral medulla which was blunted following Ang II infusion. Ang II evoked nuclear translocation of Nrf2 in cultured Neuro 2A (N2A) cells. In synhACE2−/− mice, the central Ang II pressor response was attenuated by simultaneous intracerebroventricular infusion of the Nrf2 activator sulforaphane; blood pressure was enhanced by knockdown of Nrf2 in the rostral ventrolateral medulla in Nrf2 floxed (Nrf2f/f) mice. These data suggest that the hypertensive effects of intracerebroventricular Ang II are attenuated by selective overexpression of brain synhACE2 and may be mediated by Nrf2-upregulated antioxidant enzymes in the rostral ventrolateral medulla.

中文翻译：

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中枢 ACE2（血管紧张素转换酶 2）的过度表达减弱了对慢性中枢性血管紧张素 II（血管紧张素 II）输注的升压反应

补充数字内容在文本中可用。我们研究了 ACE2（血管紧张素转换酶 2）过表达改变神经体液流出和中枢氧化应激的机制。Nrf2（核因子 [类红细胞衍生 2] 样 2）是一种主要的抗氧化转录因子，可调节细胞保护和抗氧化基因。我们假设中央 ACE2 的上调通过在延髓延髓腹外侧 Nrf2/抗氧化酶介导的机制减少活性氧，从而抑制对 Ang II（血管紧张素 II）的升压反应。突触蛋白人血管紧张素转化酶 2 阳性 (SynhACE2+/+) 小鼠及其同窝对照 SynhACE2-/- 用于评估脑室内输注 Ang II 的后果。在对照小鼠中，Ang II 输注引起血压和去甲肾上腺素排泄的显着增加，以及烦渴和多尿。在 synhACE2+/+ 小鼠中，中枢 Ang II 的升压作用被完全阻断。在 SynhACE2+/+ 小鼠中，烦渴、去甲肾上腺素排泄和对中枢 Ang II 反应的氧化应激标志物也减少。MasR（Mas 受体）激动剂 Ang 1-7 和阻滞剂 A779 对血压没有影响。synhACE2+/+ 小鼠在 Ang II 输注后钝化的延髓头端腹外侧中 Nrf2 的表达增强。Ang II 在培养的神经 2A (N2A) 细胞中引起 Nrf2 的核易位。在 synhACE2-/- 小鼠中，同时脑室内输注 Nrf2 激活剂萝卜硫素可减弱中枢 Ang II 升压反应；通过在 Nrf2 floxed (Nrf2f/f) 小鼠的延髓腹外侧敲低 Nrf2，血压升高。这些数据表明，脑室内 Ang II 的高血压作用通过大脑 SynhACE2 的选择性过度表达减弱，并且可能由延髓延髓腹外侧 Nrf2 上调的抗氧化酶介导。