Neuronal over-expression of ACE2 protects brain from ischemia-induced damage.

Abstract

Angiotensin (Ang) II exaggerates cerebral injury in ischemic damage. Angiotensin-converting enzyme type 2 (ACE2) converts Ang II into Ang (1-7) and thus, may protect against the effects of Ang II. We hypothesized that neuronal ACE2 over-expression decreases ischemic stroke in mice with Ang II overproduction. Human renin and angiotensinogen double transgenic (RA) mice and RA mice with neuronal over-expression of ACE2 (SARA) were used for the study. The mean arterial pressure (MAP) was calculated from telemetry-recorded blood pressure (BP). SARA mice were infused peripherally with Norepinephrine to "clamp" the BP, or intracerebroventricularly-infused with a Mas receptor antagonist (A-779). Middle cerebral artery occlusion (MCAO) surgery was performed to induce permanent focal ischemic stroke. Cerebral blood flow (CBF) and neurological function were determined. Two days after surgery, brain samples were collected for various analyses. Results showed: 1) When compared to chronically hypertensive RA mice, SARA mice had lower basal MAP, less MCAO-induced infarct volume, and increased CBF, neurological function and cerebral microvascular density in the peri-infarct area; 2) These changes in SARA mice were not altered after MAP "clamping", but partially reversed by brain infusion of A-779; 3) Ang (1-7)/Ang II ratio, angiogenic factors, endothelial nitric oxide synthase (eNOS) expression and nitric oxide production were increased, whereas, NADPH oxidase subunits and reactive oxygen species were decreased in the brain of SARA mice. ACE2 protects brain from ischemic injury via the regulation of NADPH oxidase/eNOS pathways by changing Ang (1-7)/Ang II ratio, independently of MAP changes.

• Authors: Ji Chen, Yuhui Zhao, Shuzhen Chen, Jinju Wang, Xiang Xiao, Xiaotang Ma, Madhuri Penchikala, Huijing Xia, Eric Lazartigues, Bin Zhao, Yanfang Chen
• Journal: Neuropharmacology (Neuropharmacology) Vol. 79 Pg. 550-8 (Apr 2014) ISSN: 1873-7064 [Electronic] England
• PMID: 24440367 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• 7-Ala-angiotensin (1-7)
• Neuroprotective Agents
• Peptide Fragments
• Angiotensinogen
• Angiotensin II
• Peptidyl-Dipeptidase A
• ACE2 protein, human
• Ace2 protein, mouse
• Angiotensin-Converting Enzyme 2
• Renin

Topics

• Angiotensin II (analogs & derivatives, pharmacology)
• Angiotensin-Converting Enzyme 2
• Angiotensinogen (genetics, metabolism)
• Animals
• Arterial Pressure (drug effects, physiology)
• Brain (drug effects, pathology, physiopathology)
• Brain Ischemia (drug therapy, pathology, physiopathology)
• Cerebrovascular Circulation (drug effects, physiology)
• Humans
• Infarction, Middle Cerebral Artery (drug therapy, pathology, physiopathology)
• Male
• Mice
• Mice, Transgenic
• Neurons (drug effects, pathology, physiology)
• Neuroprotective Agents (pharmacology)
• Peptide Fragments (pharmacology)
• Peptidyl-Dipeptidase A (genetics, metabolism)
• Renin (genetics, metabolism)