Classical renin-angiotensin system (RAS) is mainly known as angiotensin (Ang) converting enzyme (ACE)/Ang II/Ang type 1 (AT1) receptor axis which induces various organ damages including cognitive decline. On the other hand, ACE2/Ang-(1–7)/Mas axis has been known to exert antagonistic actions against the classical RAS axis in cardiovascular system. However, the roles of ACE2/Ang-(1–7)/Mas axis in cognitive function remain to be elucidated. Here, we examined possible roles of ACE2/Ang-(1–7)/Mas axis in cognitive function in vascular dementia model.Design and Method:
Male 10-week-old C57BL6 (wild-type: WT) mice, Mas1 knockout (MasKO) mice, Angiotensin type2 receptor knockout (AT2KO) mice and AT2/Mas1 double KO (WKO) mice were all conducted bilateral carotid artery stenosis (BCAS) surgery. After 6 week of surgery they were subjected to the Morris water maze task for cognitive function. Cerebral blood flow (CBF) was analyzed by laser speckle flowmetry after the cognitive task. Receptor expressions and inflammatory cytokine levels were determined by real-time RT-PCR.Results:
Spatial cognitive function was significantly impaired in AT2KO mice and WKO mice compared with WT mice after BCAS (As shown in Figure 1). On the other hand, MasKO mice showed no deterioration in cognitive function after BCAS surgery even though their CBF were significantly lower than sham-operated mice. Receptor expression of AT1, AT2 receptors and MAS showed no difference between groups. There were no significant differences between groups in inflammatory cytokine expressions.Conclusions:
These results indicate that AT2 receptor signal plays more important role in maintenance of cognitive function than Mas receptor signal does. In ischemic brain conditions, whether ACE2/Ang-(1–7)/Mas axis has protective effect or not should be assessed carefully. Further investigation is necessary to understand the detailed mechanism.