Abstract P450: AT2 Receptor Stimulation Reduces Ischemic Brain Damage Through AT2 Receptor-interacting Protein Signal

Abstract

Objectives: We reported the preventive effects of angiotensin II type 2 (AT2) receptor stimulation on ischemic brain damage. Moreover, we have cloned ATIP (AT2 receptor interacting protein) as a protein interacting specifically with the C-terminal tail of the AT2 receptor, and suggest that ATIP should play key roles in diverse mechanisms of AT2 receptor actions. However, the effect of ATIP on ischemic brain damage is unclear. Therefore, we investigated the effects of the ATIP and compound 21 (C21), a selective non-peptide AT2 receptor agonist, on focal cerebral ischemia. Method: Ten-week-old male ATIP-transgenic (ATIP-Tg) and littermate (WT) mice were subjected to middle cerebral artery occlusion (MCAO) with silicon-coated micro-filament. C21 (10 μg/kg/day) was administered 2 weeks before MCAO. Twenty-four hours after MCAO, ischemic volume was determined and depicted as mm 3 . Expression of methyl methanesulfonate sensitive 2 (MMS2) mRNA as a neuroprotective factor was determined by real-time RT-PCR. Cerebral blood flow (CBF) before and after MCA occlusion were measured by laser speckle flowmetry. Collateral circulation was evaluated by the perfusion of India ink. Results: Systolic blood pressure did not differ among all groups. There was no significant difference in ischemic size without C21 treatment between two strains (WT, 80 mm 3 ; ATIP-Tg, 75 mm 3 ). Treatment with C21 significantly decreased ischemic size in both strains (WT, 66 mm 3 ; ATIP-Tg, 50 mm 3 ). Interestingly, this protective effect of C21 was more marked in ATIP-Tg compared with WT mice (WT, 16% (66 of 80); ATIP-Tg, 27% (50 of 75) reduction, respectively). MMS2 expression increased in ipsilateral hemisphere of ATIP-Tg mice compared with contralateral hemisphere. There were no significant differences in CBF of core region of ischemic area, among all groups. However, the reduction of CBF in penumbra region after MCA occlusion was attenuated in ATIP-Tg mice with C21 administration. Treatment with C21 tended to increase the cerebral collateral number before MCA occlusion in ATIP-Tg mice not in WT. Conclusions: These results suggested that ATIP could enhance the cerebral protective effects of AT 2 receptor stimulation at least in part due to the increase of CBF and MMS2 expression after ischemia.