Receptor-based modulation of cardiovascular disease in the process of aging

• Project/Area Number: 25460906
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General internal medicine(including psychosomatic medicine)
• Research Institution: Yokohama City University
• Principal Investigator: KANAOKA Tomohiko 横浜市立大学, 医学(系)研究科(研究院), 客員研究員 (70551258)
• Co-Investigator(Kenkyū-buntansha): TOYA Yoshiyuki 横浜市立大学, 附属病院, 准教授 (30237143) ; TAMURA Kouichi 横浜市立大学, 医学部, 准教授 (40285143)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 受容体 / シグナル伝達 / 生理活性 / 循環器・高血圧 / トランスレーショナルリサーチ / 生体分子

Outline of Final Research Achievements

In the course of an investigational search for a fine means to regulate AT1R signaling at the local tissue sites, we have focused our analysis on the AT1R-associated protein (ATRAP), which is a molecule that directly binds to the carboxyl‐terminal domain of AT1R. In contrast to the classical components of the renin-angiotensin system (i.e. angiotensinogen, renin and AT1R), alteration of ATRAP expression exerts no evident effects on baseline BP and renal morphology and function in vivo such as in ATRAP-transgenic mice and ATRAP-deficient mice in physiological condition. However, accumulating experimental results in these mice indicate that ATRAP exerts inhibitory effects on the exaggerated activation of tissue AT1R signaling in response to pathological stimuli, in order to protect cardiovascular and renal tissues under pathological conditions, in spite of no influence of ATRAP on physiological AT1R signaling.

Research Products

• [Journal Article] TLR4 as a possible key regulator of pathological vascular remodeling by Ang II receptor activation. (2016)
  • Author(s): Tamura K, Kanaoka T, Kobayashi R, Ohki K, Ohsawa M.
  • Journal Title: Hypertens Res. Volume: 38 Issue: 10 Pages: 642-643
  • DOI: 10.1038/hr.2015.65
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of pitavastatin add-on therapy on chronic kidney disease with albuminuria and dyslipidemia. (2015)
  • Author(s): Ohsawa M, Tamura K, Wakui H, Kanaoka T, Azushima K, Uneda K, Haku S, Kobayashi R, Ohki K, Haruhara K, Kinguchi S, Toya Y, Umemura S.
  • Journal Title: Lipids Health Dis. Volume: 14 Issue: 1 Pages: 161-161
  • DOI: 10.1186/s12944-015-0164-5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effects of the oriental herbal medicine Bofu-tsusho-san in obesity hypertension: a multicenter, randomized, parallel-group controlled trial. (2015)
  • Author(s): Azushima K, Tamura K, Haku S, Wakui H, Kanaoka T, Ohsawa M, Uneda K, Kobayashi R, Ohki K, Dejima T, Maeda A, Hashimoto T, Oshikawa J, Kobayashi Y, Nomura K, Azushima C, Takeshita Y, Fujino R, Uchida K, Shibuya K, Ando D, Tokita Y, Fujikawa T, Toya Y, Umemura S.
  • Journal Title: Atherosclerosis. Volume: 240 Issue: 1 Pages: 297-304
  • DOI: 10.1016/j.atherosclerosis.2015.01.025
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Renal Tubule Angiotensin II Type 1 Receptor-Associated Protein Promotes Natriuresis and Inhibits Salt-Sensitive Blood Pressure Elevation. (2015)
  • Author(s): Wakui H, Uneda K, Tamura K, Ohsawa M, Azushima K, Kobayashi R, Ohki K, Dejima T, Kanaoka T, Tsurumi-Ikeya Y, Matsuda M, Haruhara K, Nishiyama A, Yabana M, Fujikawa T, Yamashita A, Umemura S.
  • Journal Title: J Am Heart Assoc. Volume: 19;4(3) Issue: 3 Pages: 1-14
  • DOI: 10.1161/jaha.114.001594
  • Peer Reviewed / Open Access
• [Journal Article] Effects of the Angiotensin receptor blocker olmesartan on adipocyte hypertrophy and function in mice with metabolic disorders. (2014)
  • Author(s): Maeda A, Tamura K, Wakui H, Ohsawa M, Azushima K, Uneda K, Kanaoka T, Kobayashi R, Ohki K, Matsuda M, Tsurumi-Ikeya Y, Yamashita A, Tokita Y, Umemura S.
  • Journal Title: Biomed Res Int. Volume: 2014 Pages: 946492-946492
  • DOI: 10.1155/2014/946492
  • Peer Reviewed / Open Access
• [Journal Article] Effects of Ang II receptor blocker irbesartan on adipose tissue function in mice with metabolic disorders. (2014)
  • Author(s): Maeda A, Tamura K, Wakui H, Ohsawa M, Azushima K, Uneda K, Kobayashi R, Tsurumi-Ikeya Y, Kanaoka T, Dejima T, Ohki K, Haku S, Yamashita A, Umemura S.
  • Journal Title: Int J Med Sci. Volume: 11(6) Issue: 6 Pages: 646-51
  • DOI: 10.7150/ijms.8577
  • Peer Reviewed / Open Access
• [Journal Article] Effects of single pill-based combination therapy of amlodipine and atorvastatin on within-visit blood pressure variability and parameters of renal and vascular function in hypertensive patients with chronic kidney disease. (2014)
  • Author(s): Azushima K, Uneda K, Tamura K, Wakui H, Ohsawa M, Kobayashi R, Dejima T, Kanaoka T, Maeda A, Toya Y, Umemura S.
  • Journal Title: Biomed Res Int. Volume: 2014 Pages: 437087-437087
  • DOI: 10.1155/2014/437087
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Deletion of the angiotensin II type 1 receptor-associated protein enhances renal sodium reabsorption and exacerbates angiotensin II-mediated hypertension. (2013)
  • Author(s): Ohsawa M, Tamura K, Wakui H, Maeda A, Dejima T, Kanaoka T, Azushima K, Uneda K, Tsurumi-Ikeya Y, Kobayashi R, Matsuda M, Uchida S, Toya Y, Kobori H, Nishiyama A, Yamashita A, Ishikawa Y, Umemura S.
  • Journal Title: Kidney Int. Volume: 86(3) Issue: 3 Pages: 570-81
  • DOI: 10.1038/ki.2014.95
  • Peer Reviewed / Open Access
• [Journal Article] Angiotensin receptor-binding protein ATRAP/Agtrap inhibits metabolic dysfunction with visceral obesity. (2013)
  • Author(s): Maeda A, Tamura K, Wakui H, Dejima T, Ohsawa M, Azushima K, Kanaoka T, Uneda K, Matsuda M, Yamashita A, Miyazaki N, Yatsu K, Hirawa N, Toya Y, Umemura S.
  • Journal Title: J Am Heart Assoc. Volume: 2(4) Issue: 4
  • DOI: 10.1161/jaha.113.000312
  • Peer Reviewed / Open Access
• [Journal Article] Upstream stimulatory factors 1 and 2 mediate the transcription of angiotensin II binding and inhibitory protein. (2013)
  • Author(s): Matsuda M, Tamura K, Wakui H, Maeda A, Ohsawa M, Kanaoka T, Azushima K, Uneda K, Haku S, Tsurumi-Ikeya Y, Toya Y, Maeshima Y, Yamashita A, Umemura S.
  • Journal Title: J Biol Chem. Volume: 288(26) Issue: 26 Pages: 19238-49
  • DOI: 10.1074/jbc.m113.451054
  • Peer Reviewed / Open Access
• [Journal Article] Addition of aliskiren to Angiotensin receptor blocker improves ambulatory blood pressure profile and cardiorenal function better than addition of benazepril in chronic kidney disease (2013)
  • Author(s): Ohsawa M, Wakui H, et al
  • Journal Title: Int J Mol Sci Volume: 14(8) Issue: 8 Pages: 15361-75
  • DOI: 10.3390/ijms140815361
  • Peer Reviewed
• [Journal Article] Umemura S.L/N-type calcium channel blocker cilnidipine added to renin-angiotensin inhibition improves ambulatory blood pressure profile and suppresses cardiac hypertrophy in hypertension with chronic kidney disease (2013)
  • Author(s): Kanaoka T, Tamura K, Wakui H, Ohsawa M, Azushima K, Uneda K, Kobayashi R, Fujikawa T, Tsurumi-Ikeya Y, Maeda A, Yanagi M, Toya Y
  • Journal Title: Int J Mol Sci Volume: 14 Issue: 8 Pages: 16866-16881
  • DOI: 10.3390/ijms140816866
  • Peer Reviewed
• [Journal Article] Bofu-tsu-shosan, an oriental herbal medicine, exerts a combinatorial favorable metabolic modulation including antihypertensive effect on a mouse model of human metabolic disorders with visceral obesity. (2013)
  • Author(s): Azushima K, Tamura K, Wakui H, Maeda A, Ohsawa M, Uneda K, Kobayashi R, Kanaoka T, Dejima T, Fujikawa T, Yamashita A, Toya Y, Umemura S.
  • Journal Title: PLoS One. Volume: 8(10) Issue: 10 Pages: e75560-e75560
  • DOI: 10.1371/journal.pone.0075560
  • Peer Reviewed / Open Access
• [Presentation] Toward development of novel therapeutic approach via functionally selective modulation of angiotensin receptor signaling: Focus on angiotensin receptor-binding protein ATRAP． (2015)
  • Author(s): 田村功一，涌井広道，小豆島健護，畝田一司，白 善雅，小林 竜，大城光二，春原浩太郎，金口 翔，大澤正人，前田晃延，金岡知彦，松田みゆき，山下暁朗，梅村 敏．
  • 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
  • Year and Date: 2015-10-10
  • Invited
• [Presentation] Angiotensin receptor-binding protein ATRAP as a possible candidate for therapeutic strategy of functionally selective modulation of angiotensin receptor signaling. (2015)
  • Author(s): Tamura K, Wakui H, Azushima K, Uneda K, Kobayashi R, Ohki K, Haku S, Haruhara K, Kinguchi S, Ohsawa M, Maeda A, Kanaoka T, Umemura S.
  • Organizer: American Heart Association and American Stroke Association Council on Hypertension 2015 Scientific Sessions.
  • Place of Presentation: Washington DC, 米国
  • Year and Date: 2015-09-16
  • Int'l Joint Research
• [Presentation] Single Pill-Based Combination Therapy with Amlodipine and Atorvastatin Improves Renal and Vascular Function and Clinic Blood Pressure Variability in Hypertension with Chronic Kidney Disease. (2014)
  • Author(s): Tamura K, Azushima K, Uneda K, Wakui H, Ohsawa M, Kobayashi R, Ohki K, Azuma K, Dejima T, Kanaoka T, Toya Y, Umemura S.
  • Organizer: American Society of Nephrology (ASN) Kidney Week 2014
  • Place of Presentation: Atlanta, USA
  • Year and Date: 2014-11-11 – 2014-11-16
• [Presentation] ENHANCEMENT OF ANGIOTENSIN II TYPE 1 RECEPTOR ASSOCIATED PROTEIN SUPPRESSES VASCULAR REMODELING AND OXIDATIVE STRESS IN ANGIOTENSIN II-MEDIATED HYPERTENSION. (2014)
  • Author(s): Wakui H, Tamura K, Kobayashi R, Uneda K, Azushima K, Ohsawa M, Dejima T, Tsurumi-Ikeya Y, Kanaoka T, Maeda A, Ishigami T, Hirawa N, Toya Y, Yabana M, Umemura S.
  • Organizer: The Joint Meeting of the European Society of Hypertension (ESH, 24th) and International Society of Hypertension (ISH, 25th)
  • Place of Presentation: Athens, Greece
  • Year and Date: 2014-06-13 – 2014-06-16
• [Presentation] CKDにおける24時間自由行動下血圧測定(ABPM)による血圧・心拍関連指標と腎機能障害増悪との関連についての研究 (2013)
  • Author(s): 金岡知彦，田村功一，藤川哲也，戸谷義幸，梅村 敏
  • Organizer: 第56回日本腎臓学会学術総会
  • Place of Presentation: 東京国際フォーラム（東京）