Effect of protective arm of the renin-angiotensin system on ischemic brain damage

• Project/Area Number: 17K10835
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Ehime University
• Principal Investigator: Iwanami Jun 愛媛大学, 医学系研究科, 准教授 (90624792)
• Co-Investigator(Kenkyū-buntansha): 堀内 正嗣 愛媛大学, 医学系研究科, 教授 (40150338) ; 茂木 正樹 愛媛大学, 医学系研究科, 教授 (20363236) ; 閔 莉娟 愛媛大学, 医学系研究科, 講師 (80726175)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: レニン・アンジオテンシン系 / アンジオテンシンII2型受容体 / 脳血管障害 / アンジオテンシンII２型受容体 / 脳保護作用 / 臓器保護作用 / 脳虚血傷害 / AT2受容体関連タンパク / 循環器・高血圧 / トランスレーショナルリサーチ

Outline of Final Research Achievements

Accumulating evidences and previous our research suggest that angiotensin II type 2 receptor(AT2R) stimulation could contribute to protection against ischemic brain damage. However, the effect of ATIP (AT2R interacting protein) on ischemic brain damage is still unclear. Therefore, we investigated the effects of the ATIP on focal cerebral ischemia using ATIP-transgenic (ATIP-Tg) mice. There was no significant difference in ischemic size between WT and ATIP-Tg mice. Treatment with AT2R agonist decreased ischemic size in both strains. Interestingly, this protective effect of AT2R agonist 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 AT2R agonist administration. These results suggested that ATIP could enhance the cerebral protective effects of AT2R stimulation after ischemia.

Academic Significance and Societal Importance of the Research Achievements

レニン・アンジオテンシン系のProtective armであるAT2受容体やACE2/Ang(1-7)/Mas系は臓器保護作用が報告されており、その活性化が注目され創薬研究として注目されている。本研究はATIPを分子標的とした独創的な研究でもあり、脳血管障害において、脳梗塞だけでなく、認知症など、さらに将来的には高血圧、糖尿病の病態解明、診断・治療の臨床医学の発展にも寄与する夢のある研究であると考えられる。

Research Products

• [Presentation] 胎児発育遅延による脳障害へのアンジオテンシンII2型受容体の保護効果 (2020)
  • Author(s): 成本悠、岩波純、単宝帥、茂木正樹、成本葵、閔莉娟、堀内正嗣
  • Organizer: 日本薬理学会
• [Presentation] ヘスペリジンは血管障害モデルマウスにおける血管リモデリングを抑制する (2020)
  • Author(s): 成本葵、岩波純、成本悠、川上萌、山口りさこ、菅野晴美、茂木正樹、閔莉娟、堀内正嗣
  • Organizer: 日本薬理学会
• [Presentation] Chronic cerebral damage aggravates vascular remodeling in cuff-induced vascular injury mouse model (2019)
  • Author(s): Jun Iwanami, Masaki Mogi, Kana Tsukuda, Akinori Higaki, Masanori Kukida, Hirotomo Nakaoka, Hui-Yu Bai, Bao-Shuai Shan, Li-Juan Min, Masatsugu Horiuchi
  • Organizer: International Stroke Conference2019
  • Int'l Joint Research
• [Presentation] AT2 receptor-interacting protein enhances protective effect of AT2 receptor stimulation in ischemic brain damage (2018)
  • Author(s): Jun Iwanami, Masaki Mogi, Xiao-Li Wang, Kana Tsukuda, Akinori Higaki, Moe Kawakami, Masanori Kukida, Hirotomo Nakaoka, Toshifumi Yamauchi, Hui-Yu Bai, Bao-Shuai Shan, Li-Juan Min, Masatsugu Horiuchi
  • Organizer: International STROKE Conference 2018
  • Int'l Joint Research
• [Presentation] Chronic cerebral ischemic injury worsens vascular dysfunction (2018)
  • Author(s): Jun Iwanami, Masaki Mogi, Kana Tsukuda, Akinori Higaki, Moe Kawakami, Masanori Kukida, Hirotomo Nakaoka, Toshifumi Yamauchi, Hui-Yu Bai, Bao-Shuai Shan, Li-Juan Min, Masatsugu Horiuchi
  • Organizer: AHA Council on Hypertension 2018
  • Int'l Joint Research
• [Presentation] AT2 receptor-interacting protein enhances protective effect of AT2 receptor stimulation in ischemic brain damage (2018)
  • Author(s): Jun Iwanami, Masaki Mogi, Xiao-Li Wang, Kana Tsukuda, Akinori Higaki, Moe Kawakami, Masanori Kukida, Hirotomo Nakaoka, Toshifumi Yamauchi, Hui-Yu Bai, Bao-Shuai Shan, Li-Juan Min and Masatsugu Horiuchi
  • Organizer: International Stroke Conference
  • Int'l Joint Research
• [Presentation] AT2 receptor stimulation reduces ischemic brain damage through AT2 receptor-interacting protein signal (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 and Masatsugu Horiuchi
  • Organizer: AHA Council on Hypertension
  • Int'l Joint Research
• [Presentation] AT2受容体相互作用タンパク質過剰発現はAT2受容体刺激による脳保護作用を増強する (2017)
  • Author(s): 岩波純、茂木正樹、佃架奈、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: 日本高血圧学会総会