Systematic Approach for the Enhancement of Cognitive Function by the Activation of Angiotensin Type 2 receptor Associated Protein

• Project/Area Number: 25293310
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Ehime University
• Principal Investigator: Horiuchi Masatsugu 愛媛大学, 医学(系)研究科(研究院), 教授 (40150338)
• Co-Investigator(Kenkyū-buntansha): Mogi Masaki 愛媛大学, 大学院医学系研究科, 准教授 (20363236) ; Iwanami Jun 愛媛大学, 大学院医学系研究科, 助教 (90624792)
• Co-Investigator(Renkei-kenkyūsha): Ohshima Kousei 愛媛大学, 医学部附属病院, 医員 (10598626)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2015: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2014: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2013: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: アンジオテンシン / 受容体 / 認知機能 / クロストーク / 受容体機能調節タンパク / 認知症 / 脳卒中 / 受容体機能調節タンク

Outline of Final Research Achievements

We observed that cognitive impairment after bilateral common carotid artery stenosis (BCAS), as a model of vascular dementia, was more marked in angiotensin type 2 (AT2) receptor knockout (KO) mice compared with that in wild-type (WT) mice, and that the overexpression of AT2 receptor interacting protein (ATIP) could protect cognitive impairment after BCAS. We also reported that angiotensin converting enzyme (ACE2) KO mice exhibited significant impairment of spatial cognitive function. These results suggest that protective arm of renin-angiotensin system (RAS) could attenuate cognitive decline after ischemic brain damage. Moreover, we proposed a new mechanism by which ATIP could plays an important roles in neurons and vascular smooth muscle cells as transcription factor as a member of protective arm of RAS.

Research Products

• [Journal Article] Angiotensin AT2-receptor stimulation improves survival and neurological outcome after experimental atroke in mice. (2016)
  • Author(s): Schwengel K, Namsolleck P, Lucht K, Clausen BH, Lambertsen KL, Valero-Esquitino V, Thöne-Reineke C, Müller S, Widdop R E, Denton KM, Horiuchi M, Iwai M, Boato F, Dahlöf B, Hallberg A, Unger T, Steckelings UM.
  • Journal Title: J Mol Med. 2016. Volume: in press Issue: 8 Pages: 957-966
  • DOI: 10.1007/s00109-016-1406-3
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Angiotensin II type 2 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: in press
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Platelet-endothelial cell interaction in brain microvessels of angiotensin II type-2 receptor knockout mice following transient bilateral common carotid artery occlusion. (2015)
  • Author(s): Fukuoka T, Hayashi T, Hirayama M, Maruyama H, Mogi M, Horiuchi M, Takao M, Tanahashi N.
  • Journal Title: J Thromb Thrombolysis Volume: 40 Issue: 4 Pages: 401-405
  • DOI: 10.1007/s11239-015-1254-y
  • Peer Reviewed / Open Access / 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] Low protein diet-induced fetal growth restriction leads to exaggerated proliferative response to vascular injury in postnatal life. (2015)
  • 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: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Angiotensin II type 2 receptor signaing 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: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Drinking citrus fruit juice inhibits vascular remodeling in cuff-induced vascular injury mouse model. (2015)
  • Author(s): Ohnishi A, Asayama R, Mogi M, Nakaoka H, Kan-no H, Tsukuda K, Chisaka T, Wang XL, Bai HY, Shan BS, Kukida M, Iwanami J, Horiuchi M.
  • Journal Title: PLoS ONE Volume: 10 Issue: 2 Pages: e0117616-e0117616
  • DOI: 10.1371/journal.pone.0117616
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis in the hypotensive effect of azilsartan. (2014)
  • Author(s): Iwanami J, Mogi M, Tsukuda K, Wang XL, Nakaoka H, Jing F, Ohshima K, Chisaka T, Bai HY, Kanno H, Min LJ, Horiuchi M.
  • Journal Title: Hypertens Res. Volume: - Issue: 7 Pages: 00015-00017
  • DOI: 10.1038/hr.2014.49
  • Peer Reviewed
• [Journal Article] Serum levels of renin-angiotensin system components in acute stroke patients. (2014)
  • Author(s): Mogi M, Kawajiri M, Tsukuda K, Matsumoto S, Yamada T, Horiuchi M.
  • Journal Title: Geriatr Gerontoi Int. Volume: 14 Issue: 4 Pages: 793-798
  • DOI: 10.1111/ggi.12167
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Direct stimulation of angiotensin II type2 receptor initiated after stroke ameliorates ischemic brain damage. (2014)
  • Author(s): Min LJ, Mogi M, Tsukuda K, Jing F, Ohshima K, Nakaoka H, Kanno H, Wang XL, Chisaka T, Bai HY, Iwanami J, Horiuchi M.
  • Journal Title: Am J Hypertens. Volume: in press
  • Peer Reviewed
• [Journal Article] Possible role of angiotensin-converting enzyme 2 and activation of angiotensin II type 2 receptor by angiotensin-(1-7) in improvement of vascular remodeling by angiotensin II type 1 receptor blockade (2014)
  • Author(s): Ohshima K, Mogi M(31人中②), et al
  • Journal Title: Hypertension Volume: 63 Issue: 3
  • DOI: 10.1161/hypertensionaha.113.02426
  • Peer Reviewed / Open Access
• [Journal Article] Possible synergistic effect of direct angiotensin II type 2 receptor stimulation by compound 21 with memantine on prevention of cognitive decline in type 2 diabetic mice. (2014)
  • Author(s): Iwanami J, Mogi M, Tsukuda K, Jing F, Ohshima K, Wang XL, Nakaoka H, Kan-no H, Chisaka T, Bai HY, Min LJ, Horiuchi M.
  • Journal Title: Eur J Pharmacol Volume: 724 Pages: 9-15
  • DOI: 10.1016/j.ejphar.2013.12.015
  • Peer Reviewed
• [Presentation] Possible epigenetic modulation of cerebral angiotensin type 2 receptor in the cognitive function in vascular dementia. (2016)
  • Author(s): Iwanami J, Mogi M, TsukudaK, Wang XL, Higaki A, Kukida M, Nakaoka H, Yamauchi T, Bai HY, Shan BS, Min LJ, Horiuchi M.
  • Organizer: INTERNATIONAL STROKE CONFERENCE 2016
  • Place of Presentation: 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): Iwanami J, Mogi M, Wang XL, TsukudaK, Higaki A, Kukida M, Nakaoka H, Yamauchi T, Bai HY, Shan BS, Min LJ, Horiuchi M.
  • Organizer: INTERNATIONAL STROKE CONFERENCE 2016
  • Place of Presentation: Los Angeles, USA
  • Year and Date: 2016-02-17
  • Int'l Joint Research
• [Presentation] Roles of angiotensin II type 2 receptor in cognitive function. (2015)
  • Author(s): Horiuchi M.
  • Organizer: 第38回日本高血圧学会総会
  • Place of Presentation: 「ひめぎんホール」愛媛県松山市、日本
  • Year and Date: 2015-10-09
  • Invited
• [Presentation] Stroke, Cognitive Function and Renin Angiotensin System. (2015)
  • Author(s): Horiuchi M.
  • Organizer: 11th Asia Pacific Congrss of Hypertension 2015
  • Place of Presentation: Bali, Indonesia
  • Year and Date: 2015-06-04
  • Int'l Joint Research / Invited
• [Presentation] Vascular Remodelling: Roles of Preotective Arm of Renin Angiotensin Syste. (2015)
  • Author(s): Horiuchi M.
  • Organizer: 11th Asia Pacific Congrss of Hypertension 2015
  • Place of Presentation: Bali, Indonesia
  • Year and Date: 2015-06-04
  • Int'l Joint Research / Invited
• [Presentation] レニン・アンジオテンシン系Protective Armと血管保護 (2015)
  • Author(s): 堀内正嗣
  • Organizer: 第15回日本抗加齢医学会総会
  • Place of Presentation: 「福岡国際会議場」福岡県福岡市、日本
  • Year and Date: 2015-05-29
  • Invited
• [Presentation] 柑橘飲料飲用による血管障害抑制効果（炎症性血管障害モデルマウスにおける検討） (2015)
  • Author(s): 大西亜里香、浅山理恵、茂木正樹、中岡裕智、菅野晴美、千阪俊行、莖田昌敬、岩波純、堀内正嗣
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] Direct angiotensin II type 2 receptor stimulation by compound 21 prevents vascular dementia (2015)
  • Author(s): Iwanami J, Mogi M, Tsukuda K, Wang XL. Kukida M, Nakaoka H, Chisaka T, Bai HY, Shan BS, Horiuchi M
  • Organizer: INTERNATIONAL STROKE CONFERENCE 2015
  • Place of Presentation: Music City Center
  • Year and Date: 2015-02-11 – 2015-02-13
• [Presentation] Effect of interferon regulatory factor-1 on vascular dementia using mouse chronic cerebral hypoperfusion model (2015)
  • Author(s): Wang XL, Iwanami J, Mogi M, Tsukuda K, Nakaoka H, Bai HY, Kukida M, Chisaka T, Shan BS ,Horiuchi M
  • Organizer: INTERNATIONAL STROKE CONFERENCE 2015
  • Place of Presentation: Music City Center
  • Year and Date: 2015-02-11 – 2015-02-13
• [Presentation] 高血圧と認知症-レニン・アンジオテンシン系の役割 (2014)
  • Author(s): 堀内正嗣
  • Organizer: 第33回日本認知症学会学術集会
  • Place of Presentation: パシフィコ横浜 会議センター
  • Year and Date: 2014-11-29 – 2014-12-01
  • Invited
• [Presentation] 新規降圧薬の動向 The current of anti- hypertensive drug targeting organ damage (2014)
  • Author(s): 堀内正嗣
  • Organizer: 第37回日本高血圧学会総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-10-17 – 2014-10-19
  • Invited
• [Presentation] インターフェロン調節因子1（IRF-1）はアンジオテンシンII2型受容体の発現を調節し、炎症性血管リモデリングを抑制する (2014)
  • Author(s): 中岡裕智、茂木正樹、菅野晴美、佃架奈、千阪俊行、莖田昌敬、王小俐、Bai Huiyu、単宝帥、岩波純、鈴木純、堀内正嗣
  • Organizer: 第37回日本高血圧学会総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-10-17 – 2014-10-19
• [Presentation] Roles of activation of angiotensin II type 2 receptor in cognitive function (2014)
  • Author(s): Horiuchi M
  • Organizer: Joint Meeting ESH-ISH HYPERTENSION ATHENS 2014
  • Place of Presentation: Megaron Athens Imternational Conference Centre
  • Year and Date: 2014-06-13 – 2014-06-16
  • Invited
• [Presentation] Hypotensive mechanism of telmisartan in high salt-loading human renin and angiotensinogen transgenic mice (2014)
  • Author(s): Iwanami J, Mogi M, Tsukuda K, Wang XL, Ohshima K, Nakaoka H, Chisaka T, Bai H, Min LJ, Horiuchi M
  • Organizer: Joint Meeting ESH-ISH HYPERTENSION ATHENS 2014
  • Place of Presentation: Megaron Athens Imternational Conference Centre
  • Year and Date: 2014-06-13 – 2014-06-16
• [Presentation] Synergistic inhibitory effect of rosuvastatin and an AT2 receptor agonist on vascular remodeling (2014)
  • Author(s): Bai H, Mogi M, Nakaoka H, Kan-no H, Tsukuda K, Ohshima K, Chisaka T, Wang XL, Min LJ, Iwanami J, Horiuchi M
  • Organizer: Joint Meeting ESH-ISH HYPERTENSION ATHENS 2014
  • Place of Presentation: Megaron Athens Imternational Conference Centre
  • Year and Date: 2014-06-13 – 2014-06-16
• [Presentation] Intrauterine growth restriction is a risk of vascular remodeling (2014)
  • Author(s): Chisaka T, Mogi M, Nakaoka H, Ohshima K, Kan-no H, Tsukuda K, Wang XL, Bai H, Min LJ, Iwanami J, Horiuchi M
  • Organizer: Joint Meeting ESH-ISH HYPERTENSION ATHENS 2014
  • Place of Presentation: Megaron Athens Imternational Conference Centre
  • Year and Date: 2014-06-13 – 2014-06-16
• [Presentation] Improved cognitive function by angiotensin-(1-7) in ace2ko mice (2014)
  • Author(s): Wang XL, Iwanami J, Min LJ, Nakaoka H, Tsukuda K, Bai H, Ohshima K, Chisaka T, Mogi M, Horiuchi M
  • Organizer: Joint Meeting ESH-ISH HYPERTENSION ATHENS 2014
  • Place of Presentation: Megaron Athens Imternational Conference Centre
  • Year and Date: 2014-06-13 – 2014-06-16
• [Presentation] Angiotensin II type2 receptor interacting protein inhibits vascular remodeling with activation of perpxispme proliferator-activated receptor gamma (2014)
  • Author(s): Ohshima K, Mogi M, Nakaoka H, Iwanami J, Min LJ, Kan-no H, Tsukuda K, Chisaka T, Bai H, Wang XL, Ogimoto A, Higaki J, Horiuchi M
  • Organizer: Joint Meeting ESH-ISH HYPERTENSION ATHENS 2014
  • Place of Presentation: Megaron Athens Imternational Conference Centre
  • Year and Date: 2014-06-13 – 2014-06-16
• [Presentation] Gain-of-function of cognitive impairment by angiotensin-(1-7)in ACE deficient mice (2014)
  • Author(s): Wang XL, Mogi M, Iwanami J, Tsukuda K, Min LJ, Nakaoka H, Bai HY, Ohshima K, Chisaka T, Horiuchi M
  • Organizer: 第14回日本抗加齢医学会総会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-06-06 – 2014-06-08
• [Presentation] 中大脳動脈梗塞モデルにおけるAT2受容体直接刺激薬の脳保護効果 (2014)
  • Author(s): 閔莉娟、茂木正樹、佃架奈、中岡裕智、王小俐、千阪俊行、茎田昌敬、白薈鈺、単宝帥、岩波純、堀内正嗣
  • Organizer: 第14回日本抗加齢医学会総会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-06-06 – 2014-06-08
• [Presentation] ACE2/Angiotensin-(1-7)/ Mas axis plays an important role on cognitive function using ACE2-deficient mice. (2013)
  • Author(s): 王小俐、茂木正樹、岩波純、閔莉娟、佃架奈、中岡裕智、白薈鈺、菅野晴美、大島弘世、千阪俊行、堀内正嗣
  • Organizer: 脳心血管抗加齢研究会2013 併催 アンチエイジングフェスタ2013
  • Place of Presentation: 梅田スカイビル（大阪）
• [Presentation] Gain of function approach by angiotensin-(1-7) to cognitive decline in ACE2 deficient mice. (2013)
  • Author(s): Wang XL, Mogi M, Iwanami J, Tsukuda K, Min LJ, Nakaoka H, Bai H, Ohshima K, Chisaka T, Horiuchi M
  • Organizer: 第36回日本高血圧学会総会
  • Place of Presentation: 大阪国際会議場（大阪）
  • Invited
• [Presentation] 血管リモデリングにおけるACE2/アンジオテンシン（1-7）/ Mas系とアンジオテンシン（1-7）/ アンジオテンシンIIタイプ2受容体系のクロストーク (2013)
  • Author(s): 大島弘世、茂木正樹、中岡裕智、菅野晴美、佃架奈、千坂俊行、Huiyu Bai、王小俐、閔莉娟、岩波純、大木元明義、檜垣實男、堀内正嗣
  • Organizer: 第36回日本高血圧学会総会
  • Place of Presentation: 大阪国際会議場（大阪）
  • Invited
• [Presentation] アンジオテンシンIIタイプ2受容体直接刺激はPPAR-gamma活性化を伴って血管リモデリングを抑制する (2013)
  • Author(s): 大島弘世、茂木正樹、中岡裕智、閔莉娟、菅野晴美、佃架奈、千坂俊行、Huiyu Bai、王小俐、岩波純、大木元明義、檜垣實男、堀内正嗣
  • Organizer: 第36回日本高血圧学会総会
  • Place of Presentation: 大阪国際会議場（大阪）
  • Invited
• [Presentation] Possible roles of crosstalk between angiotensin-converting enzyme 2/ Angiotensin (1-7)/ Mas Axis and Angiotensin (1-7) angiotensin II type 2 receptor axis in vascular remodeling (2013)
  • Author(s): Ohshima K, Mogi M, Nakaoka H, Iwanai J, Min LJ, Tsukuda K, Kanno H, Chisaka T, Wang XL, Ogimoto A, Higaki J, Horiuchi M
  • Organizer: High Blood Pressure Research Scientific Sessions 2013
  • Place of Presentation: New Orileans Marriot, USA
  • Invited
• [Presentation] AT2受容体刺激は慢性脳低灌流による認知機能低下を改善する (2013)
  • Author(s): 岩波純、堀内正嗣
  • Organizer: VAS-COG Japan 2013 第4回日本血管性認知障害研究会
  • Place of Presentation: 東京コンファレンスセンター（東京）
  • Invited
• [Presentation] Possible Synergistic Effect of Direct Angiotensin II Type 2 Receptor Stimulation by Compound 21 with Memantine on Cognitive Impairment in Type 2 Diabetic Mouse (2013)
  • Author(s): Mogi M, Iwanami J, Nakaoka H, Tsukuda K, Ohshima K, Fei J, Wang XL, Chisaka T, Min LJ and Horiuchi M.
  • Organizer: Alzheimer's Association International Conference 2013
  • Place of Presentation: Boston Convention & Exhibition Center, USA
  • Invited
• [Presentation] Direct Angiotensin II Type 2 Receptor Stimulation by Compound 21 Prevents Vascular Dementia; Involvement of NMDA Receptor Activation (2013)
  • Author(s): Mogi M, Iwanami J, Min LJ Fei J, Tsukuda K, Ohshima K, Nakaoka H, Wang XL, Chisaka T, and Horiuchi M
  • Organizer: Alzheimer's Association International Conference 2013
  • Place of Presentation: Boston Convention & Exhibition Center, USA
  • Invited
• [Presentation] RA系抑制薬よりRA系調節薬へのパラダイムシフト (2013)
  • Author(s): 堀内正嗣
  • Organizer: 第2回臨床高血圧フォーラム
  • Place of Presentation: JPタワーホール＆カンファレンス（東京）
  • Invited
• [Book] THE PROTECTIVE ARM OF THE RENIN ANGIOTENSIN SYSTEM(RAS) (2015)
  • Author(s): Horiuchi M, Mogi M
  • Publisher: Elsevier
• [Remarks] ホームページ
  • URL: http://www.m.ehime-u.ac.jp/school/biochem1/
• [Remarks] 分子心血管生物・薬理学 HP
  • URL: http://www.m.ehime-u.ac.jp/school/biochem1/
• [Remarks] 分子心血管生物・薬理学HP
  • URL: http://www.m.ehime-u.ac.jp/school/biochem1/