Abstract WP264: Possible Epigenetic Modulation of Cerebral Angiotensin Type 2 Receptor in the Cognitive Function in Vascular Dementia

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Introduction: It is well known that activation of angiotensin type 1 (AT1) receptor results in cognitive impairment. In contrast, accumulating evidences suggest that angiotensin II type 2 (AT2) receptor stimulation might prevent cognitive impairment in mice. We recently reported that administration of compound 21, newly developed direct AT2 receptor agonist, improved cognitive decline in the mouse model of vascular dementia induced by bilateral common carotid artery stenosis (BCAS). Cerebral histone deacetylase (HDAC) 2 has been highlighted in terms of epigenetic modulation of cognitive function. These results led us to examine the effects of HDAC on AT2 receptor-mediated improvement of cognitive decline.

Methods: Ten-week-old male wild type (WT) (C57BL/6) or AT2 receptor knockout (AT2KO) mice were subjected to BCAS. HDAC inhibitor (SAHA; 25 mg/kg/day) was administrated from 4 weeks after BCAS operation. The Morris water maze task was performed 6 weeks after BCAS operation. HDAC2 and inflammatory cytokine levels in the hippocampus were determined. Cerebral blood flow (CBF) were assessed by laser speckle flowmetry.

Results: HDAC2 protein level in the hippocampus did not differ between WT and AT2KO mice at 10 weeks of age, whereas HDAC2 of AT2KO mice at 20 weeks of age was higher compared with that of WT mice. Cognitive impairment after BCAS was more marked in AT2KO mice. Treatment with SAHA attenuated BCAS-induced prolongation of escape latency in the Morris water maze test both in WT and AT2KO mice; however this effect of SAHA was more marked in AT2KO mice. Decrease in CBF after BCAS was not affected by SAHA treatment. Expression of inflammatory cytokine mRNA was increased by BCAS and this increase was attenuated by SAHA treatment.

Conclusions: We speculate that modulation of cerebral AT2 receptor could be new therapeutic tool to prevent cognitive impairment via epigenetic abnormalities.

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