Molecular analysis of angiontensin II receptor inactivation by inverse agonists

• Project/Area Number: 20390218
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Chiba University
• Principal Investigator: AKAZAWA Hiroshi Chiba University, 医学系研究科, 特任講師(常勤) (20396683)
• Co-Investigator(Renkei-kenkyūsha): KOMURO Issei 大阪大学, 医学系研究科, 教授 (30260483)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2010: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2009: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2008: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: シグナル伝達 / 循環器・高血圧 / 細胞・組織

Research Abstract

Angiotensin II (AngII) type 1 (AT_1) receptor physically interacts with other mechanosensitive molecules, which implicates functional relevance of the mutual interactions in mechanosensation by AT_1 receptor. Multivalent interactions between an inverse agonist and the AT_1 receptor cooperate to stabilize the receptor in an inactive conformation in response to the distinct processes of AngII-independent activation. Constitutive activity of AT_1 receptor contributes to cardiac remodeling independently of AngII even in vivo, when AT_1 receptor is up-regulalted in the heart, and inverse agonism of AT_1 receptor blockers provides therapeutic effects in the prevention of cardiac remodeling induced by constitutive activity of AT_1 receptor.

Research Products

• [Journal Article] Navigational error in the heart leads to premature ventricular excitation. (2011)
  • Author(s): Akazawa H, Komuro I.
  • Journal Title: J Clin Invest. 121 Pages: 513-516
  • Peer Reviewed
• [Journal Article] Navigational error in the heart leads to premature ventricular excitation. (2011)
  • Author(s): Akazawa H, et al.
  • Journal Title: J Clin Invest Volume: 121 Pages: 513-516
  • Peer Reviewed
• [Journal Article] Assessment of inverse agonism for the angiotensin II type 1 receptor. (2010)
  • Author(s): Akazawa H, Yasuda N, Miura S, Komuro I.
  • Journal Title: Methods Enzymol. 485 Pages: 25-35
  • Peer Reviewed
• [Journal Article] Promotion of CHIP-mediated p53 degradation protects the heart from ischemic injury. (2010)
  • Author(s): Naito AT, Okada S, Minamino T, Iwanaga K, Liu ML, Sumida T, Nomura S, Sahara N, Mizoroki T, Takashima A, Akazawa H, Nagai T, Shiojima I, Komuro I.
  • Journal Title: Circ Res. 106 Pages: 1692-1702
  • Peer Reviewed
• [Journal Article] Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload. (2010)
  • Author(s): Shimizu I, Minamino T, Toko H, Okada S, Ikeda H, Yasuda N, Tateno K, Moriya J, Yokoyama M, Nojima A, Koh GY, Akazawa H, Shiojima I, Kahn CR, Abel ED, Komuro I.
  • Journal Title: J Clin Invest. 120 Pages: 1506-1514
  • Peer Reviewed
• [Journal Article] Cardiac mast cells cause atrial fibrillation through PDGF-A-mediated fibrosis in pressure-overloaded mouse hearts. (2010)
  • Author(s): Liao CH, Akazawa H, Tamagawa M, Ito K, Yasuda N, Kudo Y, Yamamoto R, Ozasa Y, Fujimoto M, Wang P, Nakauchi H, Nakaya H, Komuro I.
  • Journal Title: J Clin Invest. 120 Pages: 242-253
  • Peer Reviewed
• [Journal Article] Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload. (2010)
  • Author(s): Shimizu I, Akazawa H, et al.
  • Journal Title: J Clin Invest Volume: 120 Pages: 1506-1514
  • Peer Reviewed
• [Journal Article] Promotion of CHIP-mediated p53 degradation protects the heart from ischemic injury. (2010)
  • Author(s): Naito AT, Akazawa H, et al.
  • Journal Title: Circ Res Volume: 106 Pages: 1692-1702
  • Peer Reviewed
• [Journal Article] Assessment of inverse agonism for the angiotensin II type 1 receptor. (2010)
  • Author(s): Akazawa H, et al.
  • Journal Title: Methods Enzymol Volume: 485 Pages: 25-35
  • Peer Reviewed
• [Journal Article] Cardiac mast cells cause atrial fibrillation through PDGF-A-mediated fibrosis in pressure-overloaded mouse hearts. (2010)
  • Author(s): Liao CH, Akazawa H., et al.
  • Journal Title: J Clin Invest 120 Pages: 242-253
  • Peer Reviewed
• [Journal Article] Multivalent ligand-receptor interactions elicit inverse agonist activity of AT_1 receptor blockers against stretch-induced AT_1 receptor activation. (2009)
  • Author(s): Qin Y, Yasuda N, Akazawa H, Ito K, Kudo K, Liao CH, Yamamoto R, Miura S, Saku K, Komuro I.
  • Journal Title: Hypertens Res. 232 Pages: 875-883
  • NAID: 10026123753
  • Peer Reviewed
• [Journal Article] PDK1 coordinates survival pathways and β-adrenergic response in the heart. (2009)
  • Author(s): Ito K, Akazawa H, Tamagawa M, Furukawa K, Ogawa W, Yasuda N, Kudo Y, Liao CH, Yamamoto R, Sato T, Molkentin JD, Kasuga M, Noda T, Nakaya H, Komuro I.
  • Journal Title: Proc Natl Acad Sci USA. 106 Pages: 8689-8694
  • Peer Reviewed
• [Journal Article] Mechanisms and functions of agonist-independent activation in the angiotensin II type 1 receptor. (2009)
  • Author(s): Akazawa H, Yasuda N, Komuro I.
  • Journal Title: Mol Cell Endocrinol. 302 Pages: 140-147
  • Peer Reviewed
• [Journal Article] Change Can Happen by PKA : Proteasomes in in vivo Hearts. (2009)
  • Author(s): Akazawa H, Komuro I.
  • Journal Title: J Mol Cell Cardiol. 46 Pages: 445-447
  • Peer Reviewed
• [Journal Article] Mechanisms and functions of agonist-independent activation in the angiotensin II type 1 receptor. (2009)
  • Author(s): Akazawa H., et al.
  • Journal Title: Mol Cell Endocrinol 302 Pages: 140-147
  • Peer Reviewed
• [Journal Article] PDK1 coordinates survival pathways and β-adrenergic response in the heart. (2009)
  • Author(s): Ito K, Akazawa H., et al.
  • Journal Title: Proc Natl Acad Sci USA 106 Pages: 8689-8694
  • Peer Reviewed
• [Journal Article] Multivalent ligand-receptor interactions elicit inverse agonist activity of AT_1 receptor blockers against stretch-induced AT_1 receptor activation. (2009)
  • Author(s): Qin Y, Yasusa N, Akazawa H., et al.
  • Journal Title: Hypertens Res 32 Pages: 875-883
  • NAID: 10026123753
  • Peer Reviewed
• [Journal Article] Change can happen" by PKA: proteasomes in in vivo hearts. (2009)
  • Author(s): Akazawa H
  • Journal Title: J Mol Cell Cardiol 46 Pages: 445-447
  • Peer Reviewed
• [Journal Article] Deficiency of Myo18B in mice results in embryonic lethality with cardiac myofibrillar aberrations. (2008)
  • Author(s): Ajima R, Akazawa H, Kodama M, Takeshita F, Otsuka A, Kohno T, Komuro I, Ochiya T, Yokota J.
  • Journal Title: Genes Cells. 13 Pages: 987-999
  • Peer Reviewed
• [Journal Article] Abdominal aortic pseudoaneurysm caused by prolonged methicillin-resistant Staphylococcus aureus sepsis. (2008)
  • Author(s): Utsumi T, Ohtsuka M, Uchida E, Yamaguchi H, Nakajima T, Akazawa H, Takano H, Nakaya H, Komuro I.
  • Journal Title: Int J Cardiol. 128 Pages: 294-295
  • Peer Reviewed
• [Journal Article] A novel mechanism of mechanical stress-induced angiotensin II type 1 receptor activation without the involvement of angiotensin II. (2008)
  • Author(s): Yasuda N, Akazawa H, Qin Y, Zou Y Komuro I.
  • Journal Title: Naunyn Schmiedebergs Arch. Pharmacol. 377 Pages: 933-939
  • Peer Reviewed
• [Journal Article] Takayasu arteritis evaluated by multi-slice computed tomography in an old man. (2008)
  • Author(s): Fujita T, Ohtsuka M, Uchida E, Yamaguchi H, Nakajima T, Akazawa H, Takano H, Nakaya H, Komuro I.
  • Journal Title: Int J Cardiol. 125 Pages: 286-287
  • Peer Reviewed
• [Journal Article] Takayasu arteritis evaluated by multi-slice computed tomography in an old man. (2008)
  • Author(s): Fujita T
  • Journal Title: Int J Cardiol 128 Pages: 286-287
  • Peer Reviewed
• [Journal Article] A novel mechanism of mechanical stress -induced angiotensin II type 1 receptor activation without the involvement of angiotensin II. (2008)
  • Author(s): Yasuda N
  • Journal Title: Naunyn Schmiedebergs Arch Pharmacol 37 Pages: 393-399
  • Peer Reviewed
• [Journal Article] Abdominal aortic pseudoaneurysm caused by prolonged methicillin -resistant Staphylococcus aureus sepsis. (2008)
  • Author(s): Utsumi T
  • Journal Title: Int J Cardiol 128 Pages: 294-295
  • Peer Reviewed
• [Journal Article] Deficiency of Myol8B in mice results in embryonic lethality with cardiac myofibrillar aberrations. (2008)
  • Author(s): Ajima R
  • Journal Title: Genes Cells 13 Pages: 987-999
  • Peer Reviewed
• [Presentation] Agonist-dependent and.independent activation of angiotensin II receptor in the pathogenesis of cardiovascular remodeling (2011)
  • Author(s): 赤澤宏
  • Organizer: 第75回日本循環器学会学術集会
  • Place of Presentation: 横浜市
  • Year and Date: 2011-03-19
• [Presentation] Agonist-dependent and-independent activation of angiotensin II receptor in the pathogenesis of cardiovascular remodeling. (2011)
  • Author(s): 赤澤宏
  • Organizer: 第75回日本循環器学会学術集会
  • Place of Presentation: 横浜市
  • Year and Date: 2011-03-19
• [Presentation] Agonist-dependent and.independent activation of angiotensin II receptor in the pathogenesis of cardiovascular remodeling (2010)
  • Author(s): 赤澤宏
  • Organizer: 第18回日本血管生物医学会学術集会
  • Place of Presentation: 大阪市
  • Year and Date: 2010-12-01
• [Presentation] Agonist-dependent and-independent activation of angiotensin II receptor in the pathogenesis of cardiovascular remodehng. (2010)
  • Author(s): 赤澤宏
  • Organizer: 第18回日本血管生物医学会学術集会
  • Place of Presentation: 大阪市(招待講演)
  • Year and Date: 2010-12-01
• [Presentation] 心臓リモデリングにおけるアンジオテンシンII受容体自律的活性の病因的役割 (2010)
  • Author(s): 赤澤宏
  • Organizer: 第32回日本高血圧学会総会
  • Place of Presentation: 福岡市
  • Year and Date: 2010-10-16
• [Presentation] アンジオテンシンII受容体のアゴニスト非依存的活性化と心不全 (2010)
  • Author(s): 赤澤宏
  • Organizer: 第32回日本高血圧学会総会
  • Place of Presentation: 福岡市
  • Year and Date: 2010-10-15
• [Presentation] アンジオテンシンII受容体のアゴニスト非依存的活性化と心不全 (2010)
  • Author(s): 赤澤宏
  • Organizer: 第32回日本高血圧学会総会
  • Place of Presentation: 福岡市(招待講演)
  • Year and Date: 2010-10-15
• [Presentation] Constitutive activity of angiotensin II receptor contributes to cardiac remodeling independently of angiotensin II (2010)
  • Author(s): 赤澤宏
  • Organizer: Basic Cardiovascular Sciences Conferences 2010
  • Place of Presentation: Rancho Mirage (USA)
  • Year and Date: 2010-07-20
• [Presentation] Constitutive activity of angiotensin II receptor contributes to cardiac remodeling independently of angiotensin II. (2010)
  • Author(s): 赤澤宏
  • Organizer: Basic Cardiovascular Sciences Conferences 2010
  • Place of Presentation: Rancho Mirage, USA
  • Year and Date: 2010-07-20
• [Presentation] Up-regulation of cardiac angiotensin II receptor induces ventricular remodeling independently of angiotensin II (2010)
  • Author(s): 赤澤宏
  • Organizer: 20^<th> World Congress of the International Society for Heart Research 2010
  • Place of Presentation: 京都市
  • Year and Date: 2010-05-13
• [Presentation] Up-regulation of cardiac angiotensin II receptor induces ventricular remodeling independently of angiotensin II. (2010)
  • Author(s): 赤澤宏
  • Organizer: 20^<th> World Congress of the International Society for Heart Research 2010
  • Place of Presentation: 京都市
  • Year and Date: 2010-05-13
• [Presentation] アンジオテンシンII受容体活性化の新しいパラダイム (2010)
  • Author(s): 赤澤宏
  • Organizer: 第47回日本臨床分子医学会学術集会
  • Place of Presentation: 東京都
  • Year and Date: 2010-04-10
• [Presentation] アンジオテンシンII受容体活性化の新しいパラダイム (2010)
  • Author(s): 赤澤宏
  • Organizer: 第47回日本臨床分子医学会学術集会
  • Place of Presentation: 東京都(招待講演)
  • Year and Date: 2010-04-10
• [Presentation] Agonist-independent activation of angiotensin II receptor in cardiovascular remodeling (2010)
  • Author(s): 赤澤宏
  • Organizer: International Symposium on Cardiovascular Endocrinology and Metabolism 2010
  • Place of Presentation: 奈良市
  • Year and Date: 2010-03-31
• [Presentation] Agonist-independent activation of angiotensin II receptor in cardiovascular remodeling. (2010)
  • Author(s): 赤澤宏
  • Organizer: International Symposium on Cardiovascular Endocrinology and Metabolism 2010.
  • Place of Presentation: 奈良市
  • Year and Date: 2010-03-31
• [Presentation] メカニカルストレスによるAT_1受容体活性化と心肥大 (2010)
  • Author(s): 赤澤宏
  • Organizer: 第74回日本循環器学会学術集会
  • Place of Presentation: 京都市
  • Year and Date: 2010-03-06
• [Presentation] Cardiac overexpression of angiotensin II type 1 receptor induces ventricular remodeling independently of angiotensin II (2010)
  • Author(s): 赤澤宏
  • Organizer: Gordon Research Conference (Angiotensin)
  • Place of Presentation: Ventura (USA)
  • Year and Date: 2010-02-24
• [Presentation] Cardiac overexpression of angiotensin II type 1 receptor induces ventricular remodeling independently of angiotensin II. (2010)
  • Author(s): 赤澤宏
  • Organizer: Gordon Research Conference, Angiotensin.
  • Place of Presentation: Ventura, CA, USA.
  • Year and Date: 2010-02-24
• [Presentation] アゴニスト非依存的なアンジオテンシンII受容体活性化の分子機構と役割 (2010)
  • Author(s): 赤澤宏
  • Organizer: 第39回日本心脈管作動物質学会
  • Place of Presentation: 名古屋市
  • Year and Date: 2010-02-05
• [Presentation] Agonist-independent activation of angiotensin II receptor in the pathogenesis of left ventricular remodeling (2009)
  • Author(s): 赤澤宏
  • Organizer: 第26回国際心臓研究学会(ISHR)日本部会
  • Place of Presentation: 札幌市
  • Year and Date: 2009-12-05
• [Presentation] Agonist-independent activation of angiotensin II receptor in the pathogenesis of left ventricular remodeling. (2009)
  • Author(s): 赤澤宏
  • Organizer: 第26回国際心臓研究学会(ISHR)日本部会
  • Place of Presentation: 札幌市
  • Year and Date: 2009-12-05
• [Presentation] PDK1 as a therapeutic target for gene therapy to coordinate survival pathways and β-adrenergic response in failing hearts (2009)
  • Author(s): 赤澤宏
  • Organizer: 第15回日本遺伝子治療学会年次学術集会
  • Place of Presentation: 吹田市
  • Year and Date: 2009-07-10
• [Presentation] PDK1 as a therapeutic target for gene therapy to coordinate survival pathways and b-adrenergic response in failing hearts. (2009)
  • Author(s): 赤澤宏
  • Organizer: 第15回日本遺伝子治療学会年次学術集会
  • Place of Presentation: 吹田市
  • Year and Date: 2009-07-10
• [Presentation] Conformational switch of angiotensin II type 1 receptor underlying mechanical stress-induced activation. (2009)
  • Author(s): 赤澤宏
  • Organizer: Keystone Symposium (GPCRs)
  • Place of Presentation: Killarney, Ireland
  • Year and Date: 2009-05-19
• [Presentation] Homeostatic role of Atg7 in normal and stressed hearts (2009)
  • Author(s): 赤澤宏
  • Organizer: 第73回日本循環器学会学術集会
  • Place of Presentation: 大阪市
  • Year and Date: 2009-03-22
• [Presentation] Homeostatic role of Atg7 in normal and stressed hearts. (2009)
  • Author(s): 赤澤宏
  • Organizer: 第74回日本循環器学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2009-03-22
• [Presentation] Homeostatic role of PDK-1 in the regulation of β-adrenergic response and cell survival in the hearts (2008)
  • Author(s): 赤澤宏
  • Organizer: 第12回日本心不全学会学術集会
  • Place of Presentation: 東京都
  • Year and Date: 2008-10-18
• [Presentation] Homeostatic role of PDK-1 in the regulation of β-adrenergic response and cell survival in the hearts. (2008)
  • Author(s): 赤澤宏
  • Organizer: 第12回日本心不全学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2008-10-18
• [Presentation] Conformational switch of angiotensin II type 1 receptor underlying mechanical stress-induced activation (2008)
  • Author(s): 赤澤宏
  • Organizer: Keystone Symposium (GPCRs)
  • Place of Presentation: Killarney (Ireland)
  • Year and Date: 2008-05-19
• [Presentation] インバースアゴニストによるアンジオテンシンII受容体活性の抑制機構 (2008)
  • Author(s): 赤澤宏
  • Organizer: 第5回GPCR研究会
  • Place of Presentation: 東京都
  • Year and Date: 2008-05-09
• [Presentation] インバースアゴニストによるアンジオテンシンII受容体活性の抑制機構 (2008)
  • Author(s): 赤澤宏
  • Organizer: 第5回GPCR研究会
  • Place of Presentation: 東京
  • Year and Date: 2008-05-09
• [Remarks] ホームページ等
  • URL: http://www.med.osaka-u.ac.jp/pub/cardiology/