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

Summary Background The angiotensin (Ang) converting enzyme 2 ( ACE 2)/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 ACE 2/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 ACE 2 ( 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.