OP.1B.01] IMPLICATION OF THE BENEFICIAL EFFECT BY MAS RECEPTOR DEFICIENCY IN VASCULAR DEMENTIA

Abstract

Objective: Regulation of renin-angiotensin-system (RAS) is expected to prevent the onset and progression of dementia. Angiotensin (Ang) converting enzyme (ACE) 2/Ang-(1–7)/Mas receptor axis has been highlighted as counteracting partner against the classical RAS, ACE/Ang II/Ang II type 1 (AT1) receptor axis. We recently reported that ACE2 deficiency caused deterioration of cognitive function. Mas receptor expression is abundant in hippocampus; however, the roles of Mas receptor in cognitive function are still an enigma. Our previous report indicates the role of Ang-(1–7) as a ligand for Ang II type 2 (AT2) receptor, which is known to improve cognitive function. Thus, we examined the possible roles of Mas receptor employing mouse vascular dementia model focusing on the interaction with AT2 receptor.Design and method: Male 10-week-old C57BL6 mice (wild-type, WT), Mas1 receptor knockout mice (MasKO) and AT2/Mas1 receptor double knockout mice (DKO) were subjected to bilateral carotid artery stenosis (BCAS) surgery. Six weeks after the surgery, we evaluated their cognitive functions with the Morris water maze test. Cerebral blood flow (CBF) was analyzed with laser speckle flowmetry. We also compared the effects of intraperitoneally administrated Ang-(1–7) in WT, MasKO, AT2KO and DKO on cognitive function. Results: There was no significant difference in spatial leaning memory between WT and MasKO in the Morris water maze test after BCAS surgery; however, DKO showed more impaired cognitive function than MasKO (Figure 1). CBF did not show any significant differences in each BCAS group. Administration of Ang-(1–7) did not change significantly these parameters in all BCAS group; however, Ang-(1–7) treatment tended to improve cognitive function even in MasKO mice (Figure 2). Conclusions: Our results suggested the possible protective effect of Mas receptor deficiency on vascular dementia. Administration of Ang-(1–7) could not improve the cognitive function under the deletion of AT2 receptor. Therefore, the interaction of Ang-(1–7) with AT2 receptor could contribute to maintain the cognitive function in MasKO.