Angiotensin Converting Enzyme 2/Ang‐(1–7)/Mas Axis Protects Brain from Ischemic Injury with a Tendency of Age‐dependence

• Published in: CNS neuroscience & therapeutics Vol. 20; no. 5; pp. 452 - 459
• Main Authors: Zheng, Jiao‐Lin, Li, Guang‐Ze, Chen, Shu‐Zhen, Wang, Jin‐Ju, Olson, James E., Xia, Hui‐Jing, Lazartigues, Eric, Zhu, Yu‐Lan, Chen, Yan‐Fang
• Format: Journal Article
• Language: English
• Published: Oxford Wiley-Blackwell 01.05.2014; John Wiley & Sons, Inc; John Wiley and Sons Inc
• Subjects: Age Factors; Aging; Angiotensin; Angiotensin I - metabolism; Angiotensin II - analogs & derivatives; Angiotensin II - metabolism; Angiotensin‐converting enzyme 2; Animals; Apoptosis; Biological and medical sciences; Brain - pathology; Brain - physiopathology; Brain Edema - etiology; Brain Edema - pathology; Brain Edema - physiopathology; Brain Ischemia - etiology; Brain Ischemia - pathology; Brain Ischemia - physiopathology; Cell Death - physiology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dependence; Enzymes; Female; Glucose - deficiency; Hypoxia, Brain - pathology; Hypoxia, Brain - physiopathology; Infarction, Middle Cerebral Artery - complications; Infarction, Middle Cerebral Artery - pathology; Infarction, Middle Cerebral Artery - physiopathology; Injuries of the nervous system and the skull. Diseases due to physical agents; Ischemic stroke; Male; Medical sciences; Membrane Glycoproteins - metabolism; Mice, Transgenic; NADPH oxidase; NADPH Oxidase 2; NADPH Oxidase 4; NADPH Oxidases - metabolism; Neurology; Neurons - pathology; Neurons - physiology; Neuropharmacology; Neuroprotective agent; Original; Peptide Fragments - metabolism; Peptidyl-Dipeptidase A - metabolism; Pharmacology. Drug treatments; Reactive Oxygen Species - metabolism; Rodents; Stroke; Stroke - etiology; Stroke - pathology; Stroke - physiopathology; Tissue Culture Techniques; Traumas. Diseases due to physical agents; Vascular diseases and vascular malformations of the nervous system; Cerebral infarction; Nervous system diseases; Stroke; Senescence; Angiotensin-converting enzyme 2; Enzyme; Oxidase; Cardiovascular disease; Ischemic stroke; Cerebral disorder; Vascular disease; Peptidases; Renin angiotensin system; Peptidyl-dipeptidase A; NADPH oxidase; Central nervous system disease; Angiotensin; Dependence; Brain ischemia; Aging; Hydrolases; Peptidyl-dipeptidases; Oxidoreductases; Cerebrovascular disease
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.12233

Summary Background The angiotensin (Ang) converting enzyme 2 (ACE2)/Ang‐(1‐7)/Mas receptor pathway is an important component of the renin–angiotensin system and has been suggested to exert beneficial effects in ischemic stroke. Aims This study explored whether the ACE2/Ang‐(1‐7)/Mas pathway has a protective effect on cerebral ischemic injury and whether this effect is affected by age. Methods We used three‐month and eight‐month transgenic mice with neural over‐expression of ACE2 (SA) and their age‐matched nontransgenic (NT) controls. Neurological deficits and ischemic stroke volume were determined following middle cerebral artery occlusion (MCAO). In oxygen and glucose deprivation (OGD) experiments on brain slices, the effects of the Mas receptor agonist (Ang1‐7) or antagonist (A779) on tissue swelling, Nox2/Nox4 expression reactive oxygen species (ROS) production and cell death were measured. Results (1) Middle cerebral artery occlusion ‐induced ischemic injury and neurological deficit were reduced in SA mice, especially in eight‐month animals; (2) OGD‐induced tissue swelling and cell death were decreased in SA mice with a greater reduction seen in eight‐month mice; (3) Ang‐(1–7) and A779 had opposite effects on OGD‐induced responses, which correlated with changes in Nox2/Nox4 expression and ROS production. Conclusions Angiotensin converting enzyme 2/Ang‐(1‐7)/Mas axis protects brain from ischemic injury via the Nox/ROS signaling pathway, with a greater effect in older animals.