A13024 AT2 receptor stimulation-induced protective effect on ischemic brain damage is enhanced by AT2 receptor-interacting protein

Abstract

Objectives: Angiotensin II type 2 (AT2) receptor stimulation could contribute to protection against ischemic brain damage. ATIP (AT2 receptor interacting protein) plays key roles in diverse mechanisms of AT2 receptor signaling. However, the effect of ATIP on stroke is still unclear. Here, we investigated the effects of the ATIP and compound 21 (C21), a selective non-peptidic AT2 receptor agonist, on focal cerebral ischemia. Methods: 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. Expression of methyl methanesulfonate sensitive 2 (MMS2) as a neuroprotective factor increased in ipsilateral hemisphere of ATIP-Tg mice compared with contralateral hemisphere. Conclusion: 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.