The role of Nuclear Erythroid Factor 2 (Nrf-2) in vascular reactivity of normotensive and spontaneously hypertensive rats
DOI:
https://doi.org/10.33448/rsd-v11i3.25646Keywords:
Hypertension; SHR; Aorta; Oxidative stress; Nrf-2.Abstract
The uncontrolled production of the reactive oxygen species (ROS) generates oxidative stress and the development of chronic diseases, such as hypertension. Antioxidant enzymes can reduce the cellular level of ROS. Nuclear erythroid factor 2 (Nrf-2) favors the expression and activity of antioxidant enzymes. In hypertensive rats, Nrf-2 expresssion appears to be reduced in blood vessels and, consequently, it favors the oxidative stress and vascular dysfunction. Apocynin (APO) has been considered a new antioxidant drug. APO reduces blood pressure, decreases ROS production, and improves endothelial function in spontaneously hypertensive rats (SHR). We hypothesized that the role of Nrf-2 in vascular reactivity is altered in SHR and APO-treatment prevents this alteration. To test this hypothesis, we evaluated aorta reactivity to phenylephrine (PE) and acetylcholine (ACh), in the absence and presence of Brusatol, Nrf-2 inhibitor. We used aortas from normotensive Wistar rats and SHR, untreated or treated with APO. Brusatol increased the reactivity of the aortas from SHR to PE, but did not change the reactivity of Wistar rat aortas. In APO-treated SHR aortas, the effect of Brusatol was not observed. The vasodilator responses to ACh were not modified by Brusatol in aortas from normotensive or hypertensive rats, untreated or treated with APO. These results suggest that Nrf-2 is activated in the contractile response to PE. In SHR aortas, exacerbated generation of ROS induces the activation of Nrf-2. This suggestion is reinforced by the lack of Brusatol effect in APO-treated SHR aortas. As APO is an antioxidant drug, the reduction of ROS in vascular cells would not lead to Nrf-2 activation.
References
Barroso, W. K. S. et al. (2020). Brazilian Guidelines of Hypertension. Arq Bras Cardiol. 116 (3): 516-658. doi: 10.36660/abc.20201238.
Bäumer, A. T., Krüger, C. A., Falkenberg, J., Freyhaus, H. T., Rösen, R., Fink, K., & Rosenkranz, S. (2007). The NAD(P)H oxidase inhibitor apocynin improves endothelial NO/superoxide balance and lowers effectively blood pressure in spontaneously hypertensive rats: comparison to calcium channel blockade. Clin Exp Hypertens. 29 (5): 287-99. doi: 10.1080/10641960701500398.
Erejuwa, O. O., Sulaiman, S. A. A., Wahab, M. S., Sirajudeen, K. N., Salleh, S., & Gurtu, S. (2012). Honey supplementation in spontaneously hypertensive rats elicits antihypertensive effect via amelioration of renal oxidative stress. Oxid Med Cell Longev. 2012:374037. doi: 10.1155/2012/374037.
Graton, M. E., Potje, S. R., Troiano, J. A., Vale, G. T., Perassa, L. A., Nakamune, A. C. M. S., Tirapelli, C. R., Bendhack, L. M., & Antoniali, C. (2019). Apocynin alters redox signaling in conductance and resistance vessels of spontaneously hypertensive rats. Free Radic Biol Med. 134: 53-63. doi: 10.1016/j.freeradbiomed.2018.12.026.
Hayashi, T., Juliet, P. A., Kano-Hayashi, H., Tsunekawa, T., Dingqunfang, D., Sumi, D., Matsui-Hirai, H., Fukatsu, A., & Iguchi, A. (2005). NADPH oxidase inhibitor, apocynin, restores the impaired endothelial-dependent and -independent responses and scavenges superoxide anion in rats with type 2 diabetes complicated by NO dysfunction. Diabetes Obes Metab. 7 (4): 334-43. doi: 10.1111/j.1463-1326.2004.00393.x.
Javkhedkar, A. A., Quiroz, Y., Rodriguez-Iturbe, B., Vaziri, N. D., Lokhandwala, M. F., & Banday, A. A. (2015). Resveratrol restored Nrf2 function, reduced renal inflammation, and mitigated hypertension in spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol. 15;308(10):R840-6. doi: 10.1152/ajpregu.00308.2014.
Lopes, R. A., Neves, K. B., Tostes, R. C., Montezano, A. C., & Touyz, R. M. (2015). Downregulation of Nuclear Factor Erythroid 2-Related Factor and Associated Antioxidant Genes Contributes to Redox-Sensitive Vascular Dysfunction in Hypertension. Hypertension. 66 (6): 1240-50. doi: 10.1161/HYPERTENSIONAHA.115.06163.
Ma, Q. (2013). Role of nrf-2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 53: 401-26. doi: 10.1146/annurev-pharmtox-011112-140320.
McIntyre, M., Bohr, D. F., & Dominiczak, A. F. (1999). Endothelial function in hypertension: the role of superoxide anion. Hypertension. 34 (4 Pt 1): 539-45. doi: 10.1161/01.hyp.34.4.539.
Mills, K. T., Stefanescu, A., He, J. (2020). The global epidemiology of hypertension. Nat Rev Nephrol.16 (4): 223-237. doi: 10.1038/s41581-019-0244-2.
Montezano, A. C., Dulak-Lis, M., Tsiropoulou, S., Harvey, A., Briones, A. M., & Touyz, R. M. (2015). Oxidative stress and human hypertension: vascular mechanisms, biomarkers, and novel therapies. Can J Cardiol. 31 (5): 631-41. doi: 10.1016/j.cjca.2015.02.008.
Oelze, M., Knorr, M., Schuhmacher, S., & Heeren, T., Otto, C., Schulz, E., Reifenberg, K., Wenzel, P., Münzel, T., & Daiber, A. (2011). Vascular dysfunction in streptozotocin-induced experimental diabetes strictly depends on insulin deficiency. J Vasc Res. 48 (4): 275-84. doi: 10.1159/000320627.
Olayanju, A., Copple, I. M., Bryan, H. K., Edge, G. T., Sison, R. L., Wong, M. W., Lai, Z. Q., Lin, Z. X., Dunn, K., Sanderson, C. M., Alghanem, A. F., Cross, M. J., Ellis, E. C., Ingelman-Sundberg, M., Malik, H. Z., Kitteringham, N. R., Goldring, C. E. & Park, B. K (2015). Brusatol provokes a rapid and transient inhibition of Nrf2 signaling and sensitizes mammalian cells to chemical toxicity-implications for therapeutic targeting of Nrf2. Free Radic Biol Med. 78: 202-12. doi: 10.1016/j.freeradbiomed.2014.11.003.
Pechánová, O., Jendeková, L., & Vranková, S. (2009). Effect of chronic apocynin treatment on nitric oxide and reactive oxygen species production in borderline and spontaneous hypertension. Pharmacol Rep. 61 (1): 116-22. doi: 10.1016/s1734-1140(09)70013-1.
Pecorelli, A., Bocci, V., Acquaviva, A., Belmonte, G., Gardi, C., Virgili, F., Ciccoli, L., Valacchi, G. (2013). NRF2 activation is involved in ozonated human serum upregulation of HO-1 in endothelial cells. Toxicol Appl Pharmacol. 15; 267 (1): 30-40. doi: 10.1016/j.taap.2012.12.001.
Perassa, L. A., Graton, M. E., Potje, S. R., Troiano, J. A., Lima, M. S., Vale, G. T., Pereira, A. A., Nakamune, A. C., Sumida, D. H., Tirapelli, C. R., Bendhack, L. M., & Antoniali, C. (2016). Apocynin reduces blood pressure and restores the proper function of vascular endothelium in SHR. Vascul Pharmacol. 87: 38-48. doi: 10.1016/j.vph.2016.06.005.
Rosa, C. M., Gimenes, R., Campos, D. H., Guirado, G. N., Gimenes, C., Fernandes, A. A., Cicogna, A. C., Queiroz, R. M., Falcão-Pires, I., Miranda-Silva, D., Rodrigues, P., Laurindo, F. R., Fernandes, D. C., Correa, C. R., Okoshi, M. P., & Okoshi, K. (2016) Apocynin influence on oxidative stress and cardiac remodeling of spontaneously hypertensive rats with diabetes mellitus. Cardiovasc Diabetol. 1; 15 (1): 126. doi: 10.1186/s12933-016-0442-1.
Selemidis, S., Sobey, C. G., Wingler, K., Schmidt, H. H., & Drummond, G. R. (2008). NADPH oxidases in the vasculature: molecular features, roles in disease and pharmacological inhibition. Pharmacol Ther. 120 (3): 254-91. doi: 10.1016/j.pharmthera.2008.08.005.
Virdis, A., Gesi, M., & Taddei, S. (2016). Impact of apocynin on vascular disease in hypertension. Vascul Pharmacol. 87:1-5. doi: 10.1016/j.vph.2016.08.006.
Zanardo, J. L. O. F. (2020). A via Nrf2 participa da maior modulação endotelial induzida pela prenhez sobre reatividade de aortas à fenilefrina. Dissertação (Mestrado). Universidade Estadual Paulista. 86 páginas. https://repositorio.unesp.br/handle/11449/193614
Zancheta, D., Troiano, J. A., Potje, S. R., Cavalari, P., Sumida, D. H., & Antoniali, C. (2015). The PI3K-Akt-eNOS pathway is involved in aortic hyporeactivity to Phenylephrine associated with late pregnancy in spontaneously hypertensive rats. Life Sci. 1;122: 78-86. doi: 10.1016/j.lfs.2014.12.014.
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Copyright (c) 2022 Andrea Estéffane Soares Cardoso de Oliveira; Ana Carolina Gomes Lisboa; Murilo Eduardo Graton; Jessica Luiza de Oliveira Fonseca Zanardo; Cayo Antônio Soares de Almeida; Cristina Antoniali
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