ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function.
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 dys...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21818366/pdf/?tool=EBI |
| _version_ | 1831771867046739968 |
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| author | Huijing Xia Sonia Suda Sharell Bindom Yumei Feng Susan B Gurley Dale Seth L Gabriel Navar Eric Lazartigues |
| author_facet | Huijing Xia Sonia Suda Sharell Bindom Yumei Feng Susan B Gurley Dale Seth L Gabriel Navar Eric Lazartigues |
| author_sort | Huijing Xia |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T08:07:10Z |
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| id | doaj.art-9b1bf537bb3d4e0b96a8ec1db06802fd |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T08:07:10Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-9b1bf537bb3d4e0b96a8ec1db06802fd2022-12-21T18:33:07ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0167e2268210.1371/journal.pone.0022682ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function.Huijing XiaSonia SudaSharell BindomYumei FengSusan B GurleyDale SethL Gabriel NavarEric LazartiguesOxidative 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21818366/pdf/?tool=EBI |
| spellingShingle | Huijing Xia Sonia Suda Sharell Bindom Yumei Feng Susan B Gurley Dale Seth L Gabriel Navar Eric Lazartigues ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function. PLoS ONE |
| title | ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function. |
| title_full | ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function. |
| title_fullStr | ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function. |
| title_full_unstemmed | ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function. |
| title_short | ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function. |
| title_sort | ace2 mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21818366/pdf/?tool=EBI |
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