Improvement of cognitive decline by cerebral AT2 receptor and HDAC2 inhibition

• Project/Area Number: 15K19974
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurosurgery
• Research Institution: Ehime University
• Principal Investigator: Iwanami Jun 愛媛大学, 医学系研究科, 助教 (90624792)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 認知機能 / 血管性認知症 / レニン・アンジオテンシン系 / エピジェネティクス / アンジオテンシンII2型受容体 / ヒストン脱アセチル化酵素２

Outline of Final Research Achievements

Cerebral histone deacetylase (HDAC) 2 has been highlighted in terms of epigenetic modulation of cognitive function. We recently reported that angiotensin II type 2 (AT2) receptor stimulation improved cognitive decline in the mouse model （BCAS) of vascular dementia. These results led us to examine the effects of HDAC on AT2 receptor-mediated improvement of cognitive decline. 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 HDAC inhibitor attenuated BCAS-induced prolongation of escape latency in the Morris water maze test both in WT and AT2KO mice; however this effect of HDAC inhibitor was more marked in AT2KO mice. We speculate that modulation of cerebral AT2 receptor could be new therapeutic tool to prevent cognitive impairment via epigenetic abnormalities.

Research Products

• [Journal Article] Administration of bovine casein-derived peptide prevents cognitive decline in Alzheimer disease model mice. (2017)
  • Author(s): Min LJ, Kobayashi Y, Mogi M, Tsukuda K, Yamada A, Yamauchi K, Abe F, Iwanami J, Xiao JZ, Horiuchi M
  • Journal Title: PLoS One Volume: 12 Issue: 2 Pages: e0171515-e0171515
  • DOI: 10.1371/journal.pone.0171515
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Angiotensin II Type 2 Receptor Inhibits Vascular Intimal Proliferation With Activation of PPARγ (2016)
  • Author(s): Kukida M, Mogi M, Ohshima K, Nakaoka H, Iwanami J, Kanno H, Tsukuda K, Chisaka T, Min LJ, Wang XL, Bai HY, Shan BS, Higaki A, Yamauchi T, Okura T, Higaki J, Horiuchi M.
  • Journal Title: Am J Hypertens Volume: 29 Issue: 6 Pages: 727-736
  • DOI: 10.1093/ajh/hpv168
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Synergistic Inhibitory Effect of Rosuvastatin and Angiotensin II Type 2 Receptor Agonist on Vascular Remodeling. (2016)
  • Author(s): Bai HY, Mogi M, Nakaoka H, Kan-No H, Tsukuda K, Wang XL, Shan BS, Kukida M, Yamauchi T, Higaki A, Min LJ, Iwanami J, Horiuchi M
  • Journal Title: J Pharmacol Exp Ther Volume: 358 Issue: 2 Pages: 352-358
  • DOI: 10.1124/jpet.116.233148
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Diabetic mice exhibited a peculiar alteration in body composition with exaggerated ectopic fat deposition after muscle injury due to anomalous cell differentiation. (2016)
  • Author(s): Mogi M, Kohara K, Nakaoka H, Kan-No H, Tsukuda K, Wang XL, Chisaka T, Bai HY, Shan BS, Kukida M, Iwanami J, Miki T, Horiuchi M
  • Journal Title: J Cachexia Sarcopenia Muscle Volume: 7 Issue: 2 Pages: 213-224
  • DOI: 10.1002/jcsm.12044
  • Peer Reviewed / Open Access
• [Journal Article] Interferon regulatory factor 1 attenuates vascular remodeling; roles of angiotensin II type 2 receptor. (2016)
  • Author(s): Nakaoka H, Mogi M, Suzuki J, Kan-No H, Min LJ, Iwanami J, Horiuchi M.
  • Journal Title: J Am Soc Hypertens Volume: 10 Issue: 10 Pages: 811-818
  • DOI: 10.1016/j.jash.2016.07.005
  • Peer Reviewed / Open Access
• [Journal Article] Enhancement of Adipocyte Browning by Angiotensin II Type 1 Receptor Blockade. (2016)
  • Author(s): Tsukuda K, Mogi M, Iwanami J, Kanno H, Nakaoka H, Wang XL, Bai HY, Shan BS, Kukida M, Higaki A, Yamauchi T, Min LJ, Horiuchi M
  • Journal Title: PLoS One Volume: 11 Issue: 12 Pages: e0167704-e0167704
  • DOI: 10.1371/journal.pone.0167704
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Low-Protein Diet-Induced Fetal Growth Restriction Leads to Exaggerated Proliferative Response to Vascular Injury in Postnatal Life. (2016)
  • Author(s): Chisaka T, Mogi M, Nakaoka H, Kan-No H, Tsukuda K, Wang XL, Bai HY, Shan BS, Kukida M, Iwanami J, Higaki T, Ishii E, Horiuchi M.
  • Journal Title: Am J Hypertens Volume: 29 Issue: 1 Pages: 54-62
  • DOI: 10.1093/ajh/hpv072
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Direct angiotensin II type 2 receptor stimulation by compound 21 prevents vascular dementia. (2015)
  • Author(s): Iwanami J, Mogi M, Tsukuda K, Wang XL, Nakaoka H, Kan-no H, Chisaka T, Bai HY, Shan BS, Kukida M, Horiuchi M.
  • Journal Title: J Am Soc Hypertens Volume: 9 Issue: 4 Pages: 250-256
  • DOI: 10.1016/j.jash.2015.01.010
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Angiotensin II type 2 receptor signaling affects dopamine levels in the brain and prevents binge eating disorder. (2015)
  • Author(s): Nakaoka H, Mogi M, Kan-No H, Tsukuda K, Ohshima K, Wang XL, Chisaka T, Bai HY, Shan BS, Kukida M, Iwanami J, Horiuchi M
  • Journal Title: J Renin Angiotensin Aldosterone Syst Volume: 16 Issue: 4 Pages: 749-757
  • DOI: 10.1177/1470320315573680
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] e-treatment with LCZ696, an orally active angiotensin receptor neprilysin inhibitor, prevents ischemic brain damage. (2015)
  • Author(s): Bai HY, Mogi M, Nakaoka H, Kan-No H, Tsukuda K, Chisaka T, Wang XL, Kukida M, Shan BS, Yamauchi T, Higaki A, Iwanami J, Horiuchi M.
  • Journal Title: Eur J Pharmacol Volume: 762 Pages: 293-298
  • DOI: 10.1016/j.ejphar.2015.05.059
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Angiotensin II Type 2 Receptor Inhibits Vascular Intimal Proliferation With Activation of PPARγ. (2015)
  • Author(s): Kukida M, Mogi M, Ohshima K, Nakaoka H, Iwanami J, Kanno H, Tsukuda K, Chisaka T, Min LJ, Wang XL, Bai HY, Shan BS, Higaki A, Yamauchi T, Okura T, Higaki J, Horiuchi M.
  • Journal Title: Am J Hypertens Volume: 印刷中
  • Acknowledgement Compliant
• [Presentation] AT2 receptor stimulation reduces stroke size in concert with AT2 receptor-interacting protein (2017)
  • Author(s): Jun Iwanami, Masaki Mogi, Xiao-Li Wang, Kana Tsukuda, Akinori Higaki, Masanori Kukida, Hirotomo Nakaoka, Toshifumi Yamauchi, Hui-Yu Bai, Bao-Shuai Shan, Li-Juan Min, Masatsugu Horiuchi
  • Organizer: International STROKE Conference 2017
  • Place of Presentation: George R. Brown Convention Center (Houston, USA)
  • Year and Date: 2017-02-22
  • Int'l Joint Research
• [Presentation] Attenuation of Stroke Damage by Angiotensin II Type 2 Receptor Stimulation via Peroxisome Proliferator-Activated Receptor-gamma Activation (2017)
  • Author(s): Jun Iwanami, Bao-Shuai Shan, Masaki Mogi, Hui-Yu Bai, Masayoshi Kukida, Toshihiro Yamauchi, Akinori Higaki, Li-Juan Min, Masatsugu Horiuchi
  • Organizer: International STROKE Conference 2017
  • Place of Presentation: George R. Brown Convention Center (Houston, USA)
  • Year and Date: 2017-02-22
  • Int'l Joint Research
• [Presentation] AT2 receptor-interacting protein ameliorates cognitive deficit induced by chronic cerebral hypoperfusio (2016)
  • Author(s): Jun Iwanami, Masaki Mogi, Xiao-Li Wang, Kana Tsukuda, Akinori Higaki, Masanori Kukida, Hirotomo Nakaoka, Toshifumi Yamauchi, Hui-Yu Bai, Bao-Shuai Shan, Li-Juan Min, Masatsugu Horiuchi
  • Organizer: VAS-COG2016
  • Place of Presentation: VU Medical Center (Amsterdam, The Netherlands)
  • Year and Date: 2016-10-11
  • Int'l Joint Research
• [Presentation] Cognitive Impairment in Angiotensin Converting Enzyme 2 Deficient Mice (2016)
  • Author(s): Jun Iwanami, Masaki Mogi, Xiao-Li Wang, Kana Tsukuda, Akinori Higaki, Masanori Kukida, Hirotomo Nakaoka, Toshifumi Yamauchi, Hui-Yu Bai, Bao-Shuai Shan, Li-Juan Min, Masatsugu Horiuchi
  • Organizer: 26th European Meeting on Hypertension and Cardiovascular Protection
  • Place of Presentation: Palais des Congrès de Paris (Paris, France)
  • Year and Date: 2016-06-10
  • Int'l Joint Research
• [Presentation] Cerebral AT2 receptor-interacting protein enhances protective effects of AT2 receptor stimulation on ischemic brain damage (2016)
  • Author(s): Jun Iwanami, Masaki Mogi, Xiao-Li Wang, Kana Tsukuda, Akinori Higaki, Masanori Kukida, Hirotomo Nakaoka, Toshifumi Yamauchi, Hui-Yu Bai, Bao-Shuai Shan, Li-Juan Min, Masatsugu Horiuchi
  • Organizer: 26th European Meeting on Hypertension and Cardiovascular Protection
  • Place of Presentation: Palais des Congrès de Paris (Paris, France)
  • Year and Date: 2016-06-10
  • Int'l Joint Research
• [Presentation] Possible Epigenetic Modulation of Cerebral Angiotensin Type 2 Receptor in the Cognitive Function in Vascular Dementia (2016)
  • Author(s): Jun Iwanami, Masaki Mogi, Kana Tsukuda, Xiao-Li Wang, Akinori Higaki, Masanori Kukida, Hirotomo Nakaoka, Toshifumi Yamauchi, Hui-Yu Bai, Bao-Shuai Shan, Li-Juan Min, Masatsugu Horiuchi
  • Organizer: International Stroke Conference
  • Place of Presentation: Los Angeles Convention Center (Los Angeles, USA)
  • Year and Date: 2016-02-17
  • Int'l Joint Research
• [Presentation] Deficiency of Angiotensin Converting Enzyme 2 Causes Deterioration of Cognitive Function (2016)
  • Author(s): Jun Iwanami, Masaki Mogi, Xiao-Li Wang, Kana Tsukuda, Akinori Higaki, Masanori Kukida, Hirotomo Nakaoka, Toshifumi Yamauchi, Hui-Yu Bai, Bao-Shuai Shan, Li-Juan Min, Masatsugu Horiuchi
  • Organizer: International Stroke Conference
  • Place of Presentation: Los Angeles Convention Center (Los Angeles, USA)
  • Year and Date: 2016-02-17
  • Int'l Joint Research
• [Presentation] 脳内ATIPによる認知機能低下予防効果 (2016)
  • Author(s): 岩波純、茂木正樹、佃架奈、王小俐、中岡裕智、檜垣彰典、莖田昌敬、山内俊史、白薈鈺、単宝帥、閔莉娟、堀内正嗣
  • Organizer: 第7回日本脳血管・認知症学会学術大会
  • Place of Presentation: 金沢都ホテル (石川県、金沢市）
• [Presentation] 脳内IRF-1欠損による認知機能への影響 (2016)
  • Author(s): 岩波純、茂木正樹、佃架奈、王小俐、中岡裕智、檜垣彰典、莖田昌敬、山内俊史、白薈鈺、単宝帥、閔莉娟、堀内正嗣
  • Organizer: 第7回日本脳血管・認知症学会学術大会
  • Place of Presentation: 金沢都ホテル (石川県、金沢市）
• [Presentation] 慢性脳低灌流モデルマウスにおける脳内ATIPの役割 (2015)
  • Author(s): 岩波純、茂木正樹、佃架奈、王小俐、中岡裕智、檜垣彰典、莖田昌敬、山内俊史、白薈鈺、単宝帥、閔莉娟、堀内正嗣
  • Organizer: 日本高血圧学会
  • Place of Presentation: ひめぎんホール （愛媛県 松山市）
  • Year and Date: 2015-10-09
• [Presentation] 脳内AT2受容体とHDAC2阻害による認知機能低下抑制効果 (2015)
  • Author(s): 岩波純、茂木正樹、佃架奈、王小俐、中岡裕智、檜垣彰典、莖田昌敬、山内俊史、白薈鈺、単宝帥、閔莉娟、堀内正嗣
  • Organizer: 日本高血圧学会
  • Place of Presentation: ひめぎんホール （愛媛 松山市）
  • Year and Date: 2015-10-09
• [Presentation] 血管性認知症モデルマウスにおける脳内AT2受容体とHDAC2阻害による改善効果 (2015)
  • Author(s): 岩波純、茂木正樹、佃架奈、王小俐、中岡裕智、檜垣彰典、莖田昌敬、山内俊史、白薈鈺、単宝帥、閔莉娟、堀内正嗣
  • Organizer: 日本脳血管・認知症学会
  • Place of Presentation: 東京ファッションタウン (東京都 江東区)
  • Year and Date: 2015-09-19
• [Presentation] 血管性認知症モデルマウスにおける脳内IRF-1の役割 (2015)
  • Author(s): 岩波純、茂木正樹、佃架奈、王小俐、中岡裕智、檜垣彰典、莖田昌敬、山内俊史、白薈鈺、単宝帥、閔莉娟、堀内正嗣
  • Organizer: 日本脳血管・認知症学会
  • Place of Presentation: 東京ファッションタウン (東京都 江東区)
  • Year and Date: 2015-09-19