The role of Nuclear Erythroid Factor 2 (Nrf-2) in vascular reactivity of normotensive and spontaneously hypertensive rats

Andrea Estéffane Soares Cardoso De Oliveira,Ana Carolina Gomes Lisboa,Cayo Antônio Soares De Almeida,Jessica Luiza De Oliveira Fonseca Zanardo,Murilo Eduardo Graton,Cristina Antoniali

doi:10.33448/rsd-v11i3.25646

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.

Highlights

Cardiovascular diseases are the leading cause of death, hospitalizations and outpatient care on a global scale.According to 2017 data, carried out by Datasus, the occurrence of deaths in Brazil reached a percentage of 27.3% for cardiovascular diseases, and hypertension was associated with 45% of the cardiac deaths: coronary artery disease and heart failure (Barroso et al, 2021)
To assess the role of Nuclear erythroid factor 2 (Nrf-2) in the vascular reactivity to PE, we compared the PE concentration-effect curves obtained in the absence and in the presence of Brusatol, an inhibitor of Nrf-2, in intact aortas from Wistar rats (Figure 1A) or spontaneously hypertensive rats (SHR) (Figure 2A)
In SHR aortas (Figure 2A), we observed that Emax of the concentration-effect curves to PE were increased in the presence of Brusatol, demonstrating that Brusatol significantly increased the reactivity of aortas from SHR

Summary

Introduction

According to 2017 data, carried out by Datasus, the occurrence of deaths in Brazil reached a percentage of 27.3% for cardiovascular diseases, and hypertension was associated with 45% of the cardiac deaths: coronary artery disease and heart failure (Barroso et al, 2021). Hypertension is a generally asymptomatic condition, and it usually evolves structural and functional changes in target organs, such as the heart, vessels, brain and kidneys. This alteration contributes to the high impact in morbidity and mortality and hospital and socioeconomic costs. There is a global need for investments in more effective antihypertensive therapies to reduce morbidity and mortality of the population (Barroso et al, 2021; Mills et al, 2020)

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