ACE2-Mediated Reduction of Oxidative Stress in the Central Nervous System Is Associated with Improvement of Autonomic Function

Huijing Xia,Dale Seth,Sharell Bindom,Yumei Feng,L Gabriel Navar,Susan B Gurley,Sonia Suda,Eric Lazartigues,Mikhail V Blagosklonny

doi:10.1371/journal.pone.0022682

Abstract

Oxidative stress in the central nervous system mediates the increase in sympathetic tone that precedes the development of hypertension. We hypothesized that by transforming Angiotensin-II (AngII) into Ang-(1–7), ACE2 might reduce AngII-mediated oxidative stress in the brain and prevent autonomic dysfunction. To test this hypothesis, a relationship between ACE2 and oxidative stress was first confirmed in a mouse neuroblastoma cell line (Neuro2A cells) treated with AngII and infected with Ad-hACE2. ACE2 overexpression resulted in a reduction of reactive oxygen species (ROS) formation. In vivo, ACE2 knockout (ACE2−/y) mice and non-transgenic (NT) littermates were infused with AngII (10 days) and infected with Ad-hACE2 in the paraventricular nucleus (PVN). Baseline blood pressure (BP), AngII and brain ROS levels were not different between young mice (12 weeks). However, cardiac sympathetic tone, brain NADPH oxidase and SOD activities were significantly increased in ACE2−/y. Post infusion, plasma and brain AngII levels were also significantly higher in ACE2−/y, although BP was similarly increased in both genotypes. ROS formation in the PVN and RVLM was significantly higher in ACE2−/y mice following AngII infusion. Similar phenotypes, i.e. increased oxidative stress, exacerbated dysautonomia and hypertension, were also observed on baseline in mature ACE2−/y mice (48 weeks). ACE2 gene therapy to the PVN reduced AngII-mediated increase in NADPH oxidase activity and normalized cardiac dysautonomia in ACE2−/y mice. Altogether, these data indicate that ACE2 gene deletion promotes age-dependent oxidative stress, autonomic dysfunction and hypertension, while PVN-targeted ACE2 gene therapy decreases ROS formation via NADPH oxidase inhibition and improves autonomic function. Accordingly, ACE2 could represent a new target for the treatment of hypertension-associated dysautonomia and oxidative stress.

Highlights

Oxidative stress is a condition of increased production of reactive oxygen species (ROS) and/or reduction of scavenging mechanisms
To determine whether Angiotensin Converting Enzyme 2 (ACE2) could be beneficial in modulating AngII-mediated ROS formation, cells were infected with AdhACE2 virus and oxidative stress assessed by DHE staining
The main new findings of this study are that ACE2 deletion, age-dependently increases ROS levels, autonomic dysfunction and blood pressure (BP), and exaggerates AngII infusion-induced oxidative stress in brain regions related to cardiovascular function

Summary

Introduction

Oxidative stress is a condition of increased production of reactive oxygen species (ROS) and/or reduction of scavenging mechanisms. Chronic systemic infusion of sub-pressor doses of AngII increases ROS production in the subfornical organ (SFO) and leads to the development of hypertension [4], which is reliant on a Rac1-dependent NAD(P)H oxidase activation [10]. Acute pressor response to central AngII has been shown to be mediated by NAD(P)H oxidase-dependent production of ROS in hypothalamic cardiovascular regulatory nuclei, including SFO and paraventricular nucleus (PVN) [5]. Taken together, these data support the proposal that ROS are important mediators in RAS-mediated activation of sympathetic tone leading to dysautonomia

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Conclusion