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Nuclear factor erythyroid factor 2 (Nrf2) transcribes genes in cultured endothelial cells that reduce reactive oxygen species (ROS) and generate nitric oxide (NO) or metabolize asymmetric dimethylarginine (ADMA), which inhibits NO synthase (NOS). Therefore, we undertook a functional study to test the hypothesis that activation of Nrf2 by tert-butylhydroquinone (tBHQ) preserves microvascular endothelial function during oxidative stress. Wild-type CB57BL/6 (wt), Nrf2 wt (+/+), or knockout (−/−) mice received vehicle (Veh) or tBHQ (0.1%; activator of Nrf2) during 14-day infusions of ANG II (to induce oxidative stress) or sham. MAP was recorded by telemetry. Mesenteric resistance arterioles were studied on isometric myographs and vascular NO and ROS by fluorescence microscopy. ANG II increased the mean arterial pressure (112 ± 5 vs. 145 ± 5 mmHg; P &lt; 0.01) and excretion of 8-isoprostane F 2α  (2.8 ± 0.3 vs. 3.8 ± 0.3 ng/mg creatinine; P &lt; 0.05) at 12–14 days. However, 12 days of ANG II reduced endothelium-derived relaxation (27 ± 5 vs. 17 ± 3%; P &lt; 0.01) and NO (0.38 ± 0.07 vs. 0.18 ± 0.03 units; P &lt; 0.01) but increased microvascular remodeling, endothelium-derived contractions (7.5 ± 0.5 vs. 13.0 ± 1.7%; P &lt; 0.01), superoxide (0.09 ± 0.03 vs. 0.29 ± 0.08 units; P &lt; 0.05), and contractions to U-46,619 (87 ± 6 vs. 118 ± 3%; P &lt; 0.05), and endothelin-1(89 ± 4 vs. 123 ± 12%; P &lt; 0.05). tBHQ prevented all of these effects of ANG II at 12–14 days in Nrf2 +/+  mice but not in Nrf2 −/−  mice. In conclusion, tBHQ activates Nrf2 to prevent microvascular endothelial dysfunction, remodeling, and contractility, and moderate ADMA and hypertension at 12–14 days of ANG II infusion, thereby preserving endothelial function and preventing hypertension.

american journal of physiology. regulatory, integrative and comparative physiology/american journal of physiology. regulatory, integrative, and comparative physiology

NRF2 prevents hypertension, increased ADMA, microvascular oxidative stress, and dysfunction in mice with two weeks of ANG II infusion