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

Wang, C., Luo, Z., Carter, G., Wellstein, A., Jose, P. A., Tomlinson, J., Leiper, J. , Welch, W. J., Wilcox, C. S. and Wang, D. (2018) NRF2 prevents hypertension, increased ADMA, microvascular oxidative stress, and dysfunction in mice with two weeks of ANG II infusion. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 314(3), R399-R406. (doi:10.1152/ajpregu.00122.2017) (PMID:29167164)

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Abstract

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 < 0.01) and excretion of 8-isoprostane F2α (2.8 ± 0.3 vs. 3.8 ± 0.3 ng/mg creatinine; P < 0.05) at 12–14 days. However, 12 days of ANG II reduced endothelium-derived relaxation (27 ± 5 vs. 17 ± 3%; P < 0.01) and NO (0.38 ± 0.07 vs. 0.18 ± 0.03 units; P < 0.01) but increased microvascular remodeling, endothelium-derived contractions (7.5 ± 0.5 vs. 13.0 ± 1.7%; P < 0.01), superoxide (0.09 ± 0.03 vs. 0.29 ± 0.08 units; P < 0.05), and contractions to U-46,619 (87 ± 6 vs. 118 ± 3%; P < 0.05), and endothelin-1(89 ± 4 vs. 123 ± 12%; P < 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.

Item Type:Articles
Additional Information:This study was supported by grants from the National Institutes of Health to C. S. Wilcox from the National Institute of Diabetes and Digestive and Kidney Diseases (DK-036079 and DK-049870) and from the National Heart, Lung, and Blood Institute (HL-068686), and by funds from the George E. Schreiner Chair of Nephrology and the Georgetown University Hypertension Center. Also, a grant from the National Heart Lung and Blood Institute (HL-134511) was given to C. S. Wilcox and D. Wang.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Leiper, Professor James
Authors: Wang, C., Luo, Z., Carter, G., Wellstein, A., Jose, P. A., Tomlinson, J., Leiper, J., Welch, W. J., Wilcox, C. S., and Wang, D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:American Journal of Physiology: Regulatory, Integrative and Comparative Physiology
Publisher:American Physiological Society
ISSN:0363-6119
ISSN (Online):1522-1490
Published Online:26 March 2018

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