title: Activation of the ACE2/Ang-(1-7)/Mas pathway reduces oxygen-glucose deprivation-induced tissue swelling, ROS production, and cell death in mouse brain with angiotensin II overproduction.
abstract: We previously demonstrated that mice which overexpress human renin and angiotensinogen (R+A+) show enhanced cerebral damage in both in vivo and in vitro experimental ischemia models. Angiotensin-converting enzyme 2 (ACE2) counteracts the effects of angiotensin (Ang-II) by transforming it into Ang-(1-7), thus reducing the ligand for the AT1 receptor and increasing stimulation of the Mas receptor. Triple transgenic mice, SARA, which specifically overexpress ACE2 in neurons of R+A+ mice were used to study the role of ACE2 in ischemic stroke using oxygen and glucose deprivation (OGD) of brain slices as an in vitro model. We examined tissue swelling, the production of reactive oxygen species (ROS), and cell death in the cerebral cortex (CX) and the hippocampal CA1 region during OGD. Expression levels of NADPH oxidase (Nox) isoforms, Nox2 and Nox4 were measured using western blots. Results show that SARA mice and R+A+ mice treated with the Mas receptor agonist Ang-(1-7) had less swelling, cell death, and ROS production in CX and CA1 areas compared to those in R+A+ animals. Treatment of slices from SARA mice with the Mas antagonist A779 eliminated this protection. Finally, western blots revealed less Nox2 and Nox4 expression in SARA mice compared with R+A+ mice both before and after OGD. We suggest that reduced brain swelling and cell death observed in SARA animals exposed to OGD result from diminished ROS production coupled with lower expression of Nox isoforms. Thus, the ACE2/Ang-(1-7)/Mas receptor pathway plays a protective role in brain ischemic damage by counteracting the detrimental effects of Ang-II-induced ROS production.
authors.affiliation: Department of Pharmacology and Toxicology, Wright State University, Boonshoft School of Medicine, Dayton, OH, United States; Department of Neurology, Second Affiliated Hospital, Harbin Medical University, China.
authors.forename: J
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Emergency Medicine, Wright State University, Boonshoft School of Medicine, Dayton, OH, United States.
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, Wright State University, Boonshoft School of Medicine, Dayton, OH, United States.
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology, Wright State University, Boonshoft School of Medicine, Dayton, OH, United States.
authors.forename: J
authors.initials: J
authors.lastname: Bihl
authors.affiliation: Department of Pharmacology and Toxicology, Wright State University, Boonshoft School of Medicine, Dayton, OH, United States.
authors.forename: J
authors.initials: J
authors.lastname: Buck
authors.affiliation: Department of Neurology, Second Affiliated Hospital, Harbin Medical University, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, LA, United States.
authors.forename: H
authors.initials: H
authors.lastname: Xia
authors.affiliation: Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, LA, United States.
authors.forename: E
authors.initials: E
authors.lastname: Lazartigues
authors.affiliation: Department of Pharmacology and Toxicology, Wright State University, Boonshoft School of Medicine, Dayton, OH, United States. Electronic address: yanfang.chen@wright.edu.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Emergency Medicine, Wright State University, Boonshoft School of Medicine, Dayton, OH, United States; Department of Neuroscience, Cell Biology and Physiology, Wright State University, Boonshoft School of Medicine, Dayton, OH, United States. Electronic address: james.olson@wright.edu.
authors.forename: J E
authors.initials: JE
authors.lastname: Olson
mesh_terms: D000803:Angiotensin I / Q000378:metabolism*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001921:Brain / Q000503:physiopathology*; D001929:Brain Edema / Q000209:etiology / Q000503:physiopathology; D002545:Brain Ischemia / Q000150:complications / Q000503:physiopathology*; D056547:CA1 Region, Hippocampal / Q000503:physiopathology; D016923:Cell Death / Q000502:physiology; D002540:Cerebral Cortex / Q000503:physiopathology; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia / Q000150:complications / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008822:Mice, Transgenic; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020521:Stroke / Q000150:complications / Q000503:physiopathology*; D046509:Tissue Culture Techniques
chemical_list: C092006:7-Ala-angiotensin (1-7); D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D000803:Angiotensin I; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7); D005947:Glucose
keywords: NADPH oxidase; brain edema; cerebral cortex; hippocampus; hypertension; stroke