Development of new heart failure treatment using DPP-4 inhibitors-The role of adenosine

• Project/Area Number: 24390203
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: KITAKAZE Masafumi 独立行政法人国立循環器病研究センター, 研究開発基盤センター, 部長 (20294069)
• Co-Investigator(Kenkyū-buntansha): ASANUMA Hiroshi 京都府立医科大学, 医学研究科, 特任准教授 (20416217) ; ASAKURA Masanori 国立循環器病研究センター, 研究開発基盤センター, 室長 (80443505) ; YAMAZAKI Satoru 国立循環器病研究センター, 研究所, 室長 (70348796)
• Research Collaborator: NAKANO Astushi ; IHARA Madoka ; MIN Kyung-Duk ; ITO Shin ; SHINDO Kazuhiro ; IMAZU Miki ; TAKAHASHI Ayako
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2014: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2013: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2012: ¥12,610,000 (Direct Cost: ¥9,700,000、Indirect Cost: ¥2,910,000)
• Keywords: アデノシン / 心不全 / トランスレーショナル研究

Outline of Final Research Achievements

It has been reported that GLP-1 and DPP-4 inhibitors improves the pathophysiology of heart failure (HF). On the other hand, adenosine is a well-established cardioprotective molecule. Interestingly, several reports have indicated that DPP-4 forms a complex with adenosine deaminase (ADA) in immune cells and that ADA regulates DPP-4-mediated intracellular signaling. Because circulating adenosine is eliminated by ADA activity, ADA inhibition by DPP-4 inhibitors may mediated cardioprotection via an adenosine-dependent mechanisms. The present study elucidated the cardioprotective mechanism of DPP-4 inhibitor in various models of HF. The increase in GLP-1 level induce by DPP-4 inhibitor reduces myocardial damage via GLP-1 receptor-mediated activation of the adenosine A1 receptor-PKC α-cAMP response element binding protein (CREB) signaling cascade in ischemia-reperfusion model. These findings support the therapeutic potential of this interaction between GLP-1 and adenosine for HF.

Research Products

• [Journal Article] An interaction between GLP-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia/reperfusion injury. (2015)
  • Author(s): Ihara M, Asanuma H, Yamazaki S, Kato H, Asano Y, Shinozaki Y, Mori H, Minamino T, Asakura M, Sugimachi M, Mochizuki N, Kitakaze M.
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: in press Issue: 10 Pages: 1287-1297
  • DOI: 10.1152/ajpheart.00835.2014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Higdla is a oositive regulaator of cytochrome c oxidase (2015)
  • Author(s): T. Hayashi, Y. Asano, Y. Shintani, H. Aoyama, H. Kioka, O. Tsukamoto, M. Hikita, K. Shinzawa-Itoh, K. Takajuji, S. Higo, H. Kato, S. Yamazaki, K. Matsuoka, A. Nakano, H. Asanuma, M. Asakura, T. Minamino, Y. Goto, T. Ogura, M. Kitakaze, I. Komuro, Y. Sakata, T. Tsukihara, S. Yoshikawa, S. Takashima
  • Journal Title: Proc. Nat. Acad. Sci. U.S.A. Volume: 112 Issue: 5 Pages: 1553-1558
  • DOI: 10.1073/pnas.1419767112
  • Peer Reviewed / Open Access
• [Journal Article] Augmented AMPK activity inhibits cell migration by phosphorylating the novel substrate Pdlim5. (2015)
  • Author(s): Yan Y, Tsukamoto O, Nakano A, Kato H, Kioka H, Ito N, Higo S, Yamazaki S, Shintani Y, Matsuoka K, Liao Y, Asanuma H, Asakura M, Takafuji K, Minamino T, Asano Y, Kitakaze M, Takashima S.
  • Journal Title: Nat Commun. Volume: 6 Issue: 1 Pages: 6137-6137
  • DOI: 10.1038/ncomms7137
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pathophysiological impact of serum fibroblast growth factor 23 in patients with nonischemic cardiac disease and early chronic kidney disease. (2014)
  • Author(s): Imazu M, Takahama H, Asanuma H, Funada A, Sugano Y, Ohara T, Hasegawa T, Asakura M, Kanzaki H, Anzai T, Kitakaze M.
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: 307(10) Issue: 10 Pages: H1504-H1511
  • DOI: 10.1152/ajpheart.00331.2014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Carperitide induces coronary vasodilation and limits infarct size in canine ischemic hearts: Role of NO. (2014)
  • Author(s): Asanuma H, Sanada S, Asakura M, Asano Y, Kim J, Shinozaki Y, Mori H, Minamino T, Takashima S,Kitakaze M.
  • Journal Title: Hypertens Res. Volume: 37(8) Issue: 8 Pages: 716-23
  • DOI: 10.1038/hr.2014.70
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Noninvasive and quantitative live imaging reveals a potential stress-responsive enhancer in the failing heart. (2014)
  • Author(s): Matsuoka K, Asano Y, Higo S, Tsukamoto O, Yan Y, Yamazaki S, Matsuzaki T, Kioka H, Kato H, Uno Y, Asakura M, Asanuma H, Minamino T, Aburatani H, Kitakaze M, Komuro I, Takashima S.
  • Journal Title: FASEB J. Volume: 28(4) Issue: 4 Pages: 1870-9
  • DOI: 10.1096/fj.13-245522
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Evaluation of intra-mitochondrial ATP levels identifies G0/G1 switch gene 2 as a positive regulator of oxidative phosphorylation (2013)
  • Author(s): Kioka H, Kato H, Fujikawa M, Tsukamoto O, Suzuki T, Imamura H, Nakano A, Higo S, Yamazaki S, Matsuzaki T, Tkafuji K, Asanuma H, Asakura M, Minamino T, Shintani Y, Yoshida M, Noji H, Kitakaze M, Komuro I, Asano Y and Takashima S
  • Journal Title: PNAS Volume: 111 Issue: 1 Pages: 273-278
  • DOI: 10.1073/pnas.1318547111
  • Peer Reviewed / Open Access
• [Journal Article] Dipeptidyl-peptidase IV inhibition improves pathophysiology of heart failure and increases survival rate in pressure-overloaded mice. (2013)
  • Author(s): Takahashi A, Asakura M, Ito S, Min KD, Shindo K, Yan Y, Liao Y, Yamazaki S, Sanada S, Asano Y, Ishibashi-Ueda H, Takashima S, Minamino T, Asanuma H, Mochizuki N, Kitakaze M
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: 304(10) Issue: 10 Pages: H1361-H1369
  • DOI: 10.1152/ajpheart.00454.2012
  • Peer Reviewed
• [Journal Article] Liposomal amiodarone augments anti-arrhythmic effects and reduces hemodynamic adverse effects in an ischemia/reperfusion rat model. (2013)
  • Author(s): Takahama H, Shigematsu H, Asai T, Matsuzaki T, Sanada S, Fu HY, Okuda K, Yamato M, Asanuma H, Asano Y, Asakura M, Oku N, Komuro I, Kitakaze M, Minamino T.
  • Journal Title: Cardiovasc Drugs Ther. Volume: 27 Issue: 2 Pages: 125-132
  • DOI: 10.1007/s10557-012-6437-6
  • Peer Reviewed
• [Journal Article] Derivation of a mathematical expression for predicting the time to cardiac events in patients with heart failure: a retrospective clinical study. (2013)
  • Author(s): Yoshida A, Asakura M, Asanuma H, Ishii A, Hasegawa T, Minamino T, Takashima S, Kanzaki H, Washio T, Kitakaze M.
  • Journal Title: Hypertens Res. Volume: 36 Issue: 5 Pages: 450-456
  • DOI: 10.1038/hr.2012.200
  • Peer Reviewed
• [Journal Article] J-WIND試験から学ぶ Evidence & Pitfall (2013)
  • Author(s): 北風政史、金智隆、浅沼博司、朝倉正紀
  • Journal Title: 医学のあゆみ Volume: 244 Pages: 1311-1316
• [Journal Article] カルシウム拮抗薬 (2013)
  • Author(s): 浅沼博司、北風政史
  • Journal Title: The Lipid Volume: 24 Pages: 43-50
• [Journal Article] Direct comparison of the diagnostic capability of cardiovascular magnetic resonance and endomyocardial biopsy in patients with heart failure (2013)
  • Author(s): Yoshida A, I shibashi-Ue da H, Yamada N, Kanzaki H, Hasegawa T, Takahama H, Amaki M, Asakura M, Kitakaze M
  • Journal Title: European Journal of Heart Failure Volume: 15 Issue: 2 Pages: 166-175
  • DOI: 10.1093/eurjhf/hfs206
  • Peer Reviewed
• [Journal Article] H(2) mediates cardioprotection via involvements of K(ATP) channels and permeability transition pores of mitochondria in dogs (2012)
  • Author(s): Yoshida A, Asanuma H, Sasaki H, Sanada S, Yamazaki S, Asano Y, Shinozaki Y, Mori H, Shimouchi A, Sano M, Asakura M, Minamino T, Takashima S, Sugimachi M, Mochizuki N, Kitakaze M.
  • Journal Title: Cardiovasc Drugs Ther. Volume: 26 Issue: 3 Pages: 217-226
  • DOI: 10.1007/s10557-012-6381-5
  • Peer Reviewed
• [Journal Article] Serum blood urea nitrogen and plasma brain natriuretic Peptide and low diastolic blood pressure predict cardiovascular morbidity and mortality following discharge in acute decompensated heart failure patients. (2012)
  • Author(s): Chen CY, Yoshida A, Asakura M, Hasegawa T, Takahama H, Amaki M, Funada A, Asanuma H, Yokoyama H,Kim J, Kanzaki H, Kitakaze M.
  • Journal Title: Circ J. Volume: 76 Pages: 2372-2379
  • NAID: 10030874757
  • Peer Reviewed
• [Journal Article] Plasma adiponectin levels predict cardiovascular events in the observational Arita Cohort Study in Japan: the importance of the plasma adiponectin levels. (2012)
  • Author(s): Chen CY, Asakura M, Asanuma H, Hasegawa T, Tanaka J, Toh N, Min KD, Kanzaki H, Takahama H, Amaki M, Itoh Y, Ichien G, Okumoto Y, Funahashi T, Kim J, Kitakaze M.
  • Journal Title: Hypertens Res. Volume: 35 Issue: 8 Pages: 843-848
  • DOI: 10.1038/hr.2012.42
  • Peer Reviewed
• [Journal Article] CB1 cannabinoid receptor deficiency promotes cardiac remodeling induced by pressure overload in mice. (2012)
  • Author(s): Liao Y, Bin J, Luo T, Zhao H, Ledent C, Asakura M, Xu D, Ta kashima S, Kitakaze M
  • Journal Title: Int J Cardiol Volume: (In press)
  • Peer Reviewed
• [Journal Article] 循環生理学・循環薬理学・分子生物学は重症心不全を救えるか (2012)
  • Author(s): 北風政史
  • Journal Title: 呼吸と循環 Volume: 60
• [Journal Article] 心筋症の分類と診断基準 (2012)
  • Author(s): 朝倉正紀,北風政史
  • Journal Title: 循環器内科 Volume: 71 Pages: 491-495
• [Journal Article] 耐糖能異常は心不全と連関するか? (2012)
  • Author(s): 浅沼博司,朝倉正紀,金智隆,北風政史
  • Journal Title: 日本冠疾患学会雑誌 Volume: 18 Pages: 245-251
  • NAID: 130001928893
  • Peer Reviewed
• [Presentation] Dipeptidyl-peptidase 4 inhibitor alogliptin attenuates myocardial ischemia/reperfusion infury via an adenosine- dependent mechanism. (2014)
  • Author(s): Ihara M, Yamazaki S, Asanuma H, Kitakaze M.
  • Organizer: 第18回日本心不全学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-10-10 – 2014-10-12
• [Presentation] The E3 Ligase Asb2 Regulates Cardiac Development Through Targeting Smad9 for Proteasomal Degradation. (2014)
  • Author(s): Min KD, Asakura M, Ito S, Shirai M, Nakano A, Tsukamoto O, Inoue H, Yamazaki S, Asanuma H, Takashima S, Minamino T, Mochizuki N, Schneider M, Kitakaze M.
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京
• [Presentation] Does the Treatment of Impaired Glucose Tolerance Provide Cardiovascular Benefits in patients with Previous Myocardial Infarction. (2014)
  • Author(s): Kitakaze M, Asakura M, Asanuma H, J-Wind Investigators.
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京
• [Presentation] Exploratory Reserch on Potential Diagnostic as Well as Therapeutic Targets for Heart Failure Using Omics Data Analysis . (2014)
  • Author(s): Asakura M, Asanuma H, Ito S, Min KD, Seguchi O, Takahashi A, Nishigori M, Shindoh K, Imazu M, Nakatani T, Tomonaga T, Minamino N, Kitakaze M.
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京
• [Presentation] Serum Fibroblast Growth Factor 23 as a Surrogate Marker in Patients with Heart Failure. (2013)
  • Author(s): 高濱博幸, 今津美樹, 浅沼博司, 舟田晃, 菅野康夫, 大原貴裕, 長谷川拓也, 朝倉正紀, 神崎秀明,安斉俊久, 北風政史
  • Organizer: 第61回日本心臓病学会学術集会
  • Place of Presentation: 熊本
• [Presentation] 次世代シーケンサーを用いた新規心不全関連遺伝子の探索 (2013)
  • Author(s): 進藤一紘, 朝倉正紀, 閔庚徳, 伊藤慎, 高橋彩子, 今津美樹, 浅沼博司, 北風政史
  • Organizer: 第61回日本心臓病学会学術集会
  • Place of Presentation: 熊本
• [Presentation] BNPは冠動脈疾患発症リスクの代用マーカーとなりうるか (2013)
  • Author(s): 長谷川拓也, 朝倉正紀, 江口和男, 浅沼博司, 天木誠, 高濱博幸, 舟田晃, 菅野康夫, 大原貴裕, 神崎秀明, 橋村一彦, 友池仁遙暢, 金智隆, 安斉俊久, 北風政史
  • Organizer: 第61回日本心臓病学会学術集会
  • Place of Presentation: 熊本
• [Presentation] Concept and Consideration for the Clinical Assessment that an AIpha-GI Blocks Cardiac Events in Patients with MI and IGT (ABC Study) (2012)
  • Author(s): Asanuma H, Asakura M, Kim J,Kitakaze M and the ABC Study Investigators.
  • Organizer: The 33rd Annual Meeting of The Japanese Society of Clinical Pharmacology and Therapeutics
  • Place of Presentation: 沖縄(招待講演)
• [Presentation] Novel synthesized radical-containing nanoparticles augment cardioprotection after ischemiareperfusion injury via nitric oxide in canine hearts (2012)
  • Author(s): Yoshida A, Sanada S, Asanuma H, Sasaki H, Takahama H, Asakura M, Yoshitomi T, Nagasaki Y,Kitakaze M.4
  • Organizer: European Society of Cardiology Congress 2012.
  • Place of Presentation: ドイツ・ミュンヘン
• [Presentation] Alteration of gene expression profiling of the murine intestine suffering from heart failure. (2012)
  • Author(s): Takahashi A, Asakura M, Min K, Ito S, Shindo K, Yan Y, Liu H, Asanuma H, Mochizuki N,Kitakaze M
  • Organizer: European Society of Cardiology Congress 2012
  • Place of Presentation: ドイツ・ミュンヘン
• [Book] 再灌流障害と心筋保護 救急医学 (2014)
  • Author(s): 浅沼博司、伊原まどか、北風政史
  • Total Pages: 124
  • Publisher: へるす出版
• [Book] 内科学第10版 (2013)
  • Author(s): 浅沼博司、北風政史
  • Total Pages: 2548
  • Publisher: 朝倉書店
• [Book] 今日の治療指針2013 (2013)
  • Author(s): 浅沼博司
  • Total Pages: 2064
  • Publisher: 医学書院
• [Book] 経静脈治療オーダーマニュアル (2012)
  • Author(s): 浅沼博司, 北風政史
  • Total Pages: 764
  • Publisher: メディカルレビュー社
• [Book] 2012-2013 EBM循環器疾患の治療 (2012)
  • Author(s): 浅沼博司, 北風政史
  • Total Pages: 424
  • Publisher: 中外医学社