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Objective: Accumulating evidences and previous our research suggest that angiotensin II type 2 (AT2) receptor stimulation could contribute to protection against ischemic brain damage. We have cloned ATIP (AT2 receptor interacting protein) as a protein interacting specifically with the C-terminal tail of the AT2 receptor, and reported that ATIP might play key roles in diverse mechanisms of AT2 receptor signaling. However, the effect of ATIP on ischemic brain damage is still unclear. Therefore, we investigated the effects of the ATIP and compound 21 (C21), a selective non-peptidic 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 area was determined. Cerebral blood flow (CBF) before and after MCAO was measured by laser speckle flowmetry. Collateral circulation was evaluated by the perfusion of India ink. Expression of mRNA was determined by real-time RT-PCR.Results: There was no significant difference in ischemic size without C21 treatment between two strains. Treatment with C21 decreased ischemic size in both strains. Interestingly, this protective effect of C21 was more marked in ATIP-Tg compared with WT mice. In CBF of core region of ischemic area, there were no significant differences among all groups. However, the reduction of CBF in penumbra region just 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. Expression of vascular endothelial growth factor (VEGF) mRNA in the cortex before MCA occlusion did not differ among all groups. Expression of methyl methanesulfonate sensitive 2 (MMS2) as a neuroprotective factor increased in ipsilateral hemisphere of ATIP-Tg mice compared with contralateral hemisphere.Conclusions: These results suggested that ATIP could enhance the cerebral protective effects of AT2 receptor stimulation at least in part due to the attenuation of CBF reduction and increase of MMS2 expression after ischemia.