title: ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function.
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.
authors.affiliation: Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Huijing
authors.initials: H
authors.lastname: Xia
authors.forename: Sonia
authors.initials: S
authors.lastname: Suda
authors.forename: Sharell
authors.initials: S
authors.lastname: Bindom
authors.forename: Yumei
authors.initials: Y
authors.lastname: Feng
authors.forename: Susan B
authors.initials: SB
authors.lastname: Gurley
authors.forename: Dale
authors.initials: D
authors.lastname: Seth
authors.forename: L Gabriel
authors.initials: LG
authors.lastname: Navar
authors.forename: Eric
authors.initials: E
authors.lastname: Lazartigues
mesh_terms: D000375:Aging / Q000473:pathology; D000804:Angiotensin II / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D017353:Gene Deletion; D015316:Genetic Therapy; D008297:Male; D051379:Mice; D009206:Myocardium / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D054969:Primary Dysautonomias / Q000473:pathology / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D014630:Vagus Nerve / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology
chemical_list: D017382:Reactive Oxygen Species; D000804:Angiotensin II; D019255:NADPH Oxidases; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2