Mechanism of GLP 1 / DDP4 in stress vascular disease and its therapeutic application

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15H04802
• Research Institution: Nagoya University
• Principal Investigator: 成 憲武 名古屋大学, 未来社会創造機構(医), 特任准教授 (30378228)
• Co-Investigator(Kenkyū-buntansha): 佐々木 健 浜松医科大学, 大学院医学系研究科, 技術専門職員 (20397433) ; 菊地 良介 名古屋大学, 医学部附属病院, 臨床検査技師 (30721435) ; 坂東 泰子 (暮石泰子) 名古屋大学, 医学部附属病院, 講師 (60452190) ; 竹下 享典 名古屋大学, 医学部附属病院, 准教授 (70444403)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 心理的ストレス / 血管新生 / 血管病 / ジペプチジルペプチダーゼ‐4

Outline of Annual Research Achievements

本研究は、DPP4の役割に着目し、マウスの拘束ストレス負荷モデルにおいて、血中と組織内でDPP4が活性化され、GLP-1の分解亢進とアディポネクチン(APN)発現低下が起こることにより、虚血骨格筋ならびに血管組織において炎症の惹起とp-AMP活性化タンパク質キナーゼ-ペルオキシソーム増殖因子活性化受容体γ（p-AMPK-PPRA-γ）/PGC-1α経路の活性化が抑制され、①下肢血流回復と毛細血管形成の低下、②大動脈の老化と血管内皮管腔形成の低下、③骨髄由来内皮前駆細胞数の減少ならびに内皮前駆細胞自体の機能不全が起こることを明らかにした。これらの変化は、DPP4遺伝子欠損や薬理学的なDPP4活性の抑制により改善したが、APN遺伝子欠損ではその改善効果が消失した。これらの結果より、慢性心理的ストレスによる血管老化の惹起と虚血組織における血管新生形成抑制作用は、DPP4 活性亢進によるGLP-1分解亢進を介してのAPN発現低下、またそれによるp-AMPK-PPRA-γ/PGC-1αシグナル経路活性化の低下と深く関係する機序を提唱し、このことを論文にまとめた。
また、申請者は、ストレス負荷による若年マウスと高齢マウスの比較研究も実施した。その結果、APN受容体１(ANPR1)発現が加齢により一層低下し、虚血骨格筋組織において炎症細胞浸潤亢進とともに、p-AMPK-PPRA-γ／PGC-1α経路活性化もより顕著に抑制され、血管新生が低下することを明らかにし、論文にまとめた（Int J Cardiol 2018/revision）。
さらに、ストレス負荷によるアテローム性動脈硬化プラークの進行・不安定化が認められた。また、病変においてTLR2/4、PPRA-α、ならびにgp91phoxの蛋白発現が亢進し、これらの変化がDPP4阻害剤投与による改善することを論文にまとめた。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] サルコペ ニアの分子メカニズム. (2018)
  • Author(s): 井上愛子、成 憲武、五籐大貴、葛谷雅文.
  • Journal Title: 日本老年医学雑誌 Volume: 55(1) Pages: 13-24
• [Journal Article] The Soluble VEGF Receptor sFlt-1 Contributes to Impaired Neovascularization in Aged Mice. (2017)
  • Author(s): Zhao G, ＊Cheng XW. Piao L, Lu L, Lei Y, Yang G, Inoue A, Ogasawara S, Wu H, Hao CN, Okumura K, Kuzuya M.
  • Journal Title: Aging and Disease. Volume: 8 Pages: 287-300
  • DOI: 10.14336/AD.2016.0920.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Exercise Restores Muscle Stem Cell Mobilization and Regenerative Capacity and Muscle Metabolic Alterations via Adiponectin/AdipoR1 Activation in SAMP10 mice. (2017)
  • Author(s): Inoue A, ＊Cheng XW, Huang Z, Hu L, Kikuchi R, Jiang H, Piao L, Sasaki T, Itakura K, Wu H, Zhao G, Lei Y, Yang G, Zhu E, Li X, Sato K, Koike T, Kuzuya M.
  • Journal Title: Journal of Cachexia, Sarcopenia and Muscle. Volume: 8 Pages: 370-385
  • DOI: 10.1002/jcsm.12166.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cardioprotective effects of PKG activation by soluble GC activator, BAY 60-2770, in ischemia-reperfusion-injured rat hearts. (2017)
  • Author(s): Lee KH, Kim W, Lee SR, Cho H, Woo JS, Kang JH, Jeong YM, Cheng XW, Kim WS.
  • Journal Title: Plos One. Volume: 12 Pages: e0180207
  • DOI: 10.1371/journal.pone.0180207.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Exenatide mitigated diet-induced vascular aging and atherosclerotic plaque growth in apoE-deficient mice under chronic stress. (2017)
  • Author(s): Yang G, Lei Y, Inoue A, Piao L, Hu L, Jiang H, Sasaki T, Zhao G, Ogasawara S, Xu W, Yu C, Wu H, Okumura K, Kuzuya M, ＊Cheng XW.
  • Journal Title: Atherosclerosis. Volume: 13 Pages: 1-10
  • DOI: 10.1016/j.atherosclerosis.2017.07.014.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dipeptidyl Peptidase-4 Regulates Hematopoietic Stem Cell Activation in Response to Chronic Stress. (2017)
  • Author(s): Zhu E, Hu L, Wu H, Piao L, Zhao G, Inoue A, Kim W, Yu C, Xu W, Bando YK, Li X, Lei Y, Hao CN, Takeshita K, Kim WS, Okumura K, Murohara T, Kuzuya M, ＊Cheng XW.
  • Journal Title: Journal of the American Heart Association. Volume: 6 Pages: e006394
  • DOI: 10.1161/JAHA.117.006394.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Increased dipeptidyl peptidase-4 accelerates diet-Related vascular aging and atherosclerosis in ApoE-deficient mice under chronic stress. (2017)
  • Author(s): Lei Y, Yang G, Hu L, Piao L, Inoue A, Jiang H, Sasaki T, Zhao G, Yisireyili M, Yu C, Xu W, Takeshita K, Okumura K, Kuzuya M, ＊Cheng XW.
  • Journal Title: International Journal of Cardiology. Volume: 24 Pages: 413-420
  • DOI: 10.1016/j.ijcard.2017.05.062.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chronic psychological stress accelerates vascular senescence and impairs ischemia-induced neovascularization: The role of dipeptidyl peptidase-4/glucagon-like peptide-1-adiponectin axis. (2017)
  • Author(s): Piao L, Zhao G, Zhu E, Inoue A, Shibata R, Lei Y, Hu L, Yu C, Yang G, Wu H, Xu W, Okumura K, Ouchi N, Murohara T, Kuzuya M, ＊Cheng XW.
  • Journal Title: Journal of the American Heart Association. Volume: 6 Pages: e006421
  • DOI: 10.1161/JAHA.117.006421.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cathepsin K Activity Controls Cardiotoxin-Induced Skeletal Muscle Repair in Mice. (2017)
  • Author(s): Ogasawara S, ＊Cheng XW, Inoue A, Hu L, Piao L, Yu C, Goto H, Xu W, Zhao G, Lei Y, Yang G, Kimura K, Umegaki H, Shi GP, Kuzuya M.
  • Journal Title: Journal of Cachexia, Sarcopenia and Muscle. Volume: - Pages: -
  • DOI: 10.1002/jcsm.12248.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Increased Dipeptidyl Peptidase-4 Accelerates Diet-Related Vascular Aging and Atherosclerosis in ApoE-Deficient Mice under Chronic Stress. (2018)
  • Author(s): Cheng XW
  • Organizer: Myocardial Ischemia Symposium in Korea 2018
  • Invited
• [Presentation] Chronic Psychological Stress Accelerates Vascular Senescence and Impairs Ischemia-induced Neovascularization: The Role of Dipeptidyl Peptidase-4/Glucagon-like Peptide-1-adiponectin Axis (2018)
  • Author(s): Limei Piao,Cheng XW
  • Organizer: 第82回日本循環器学会学術総会
• [Presentation] SAMP10マウスにおける運動と若齢マウス骨髄移植併用による加齢による筋萎縮の防止 (2017)
  • Author(s): 成憲武
  • Organizer: 第22回日本体力医学会東海地方会学術集会
  • Invited
• [Presentation] Anti-inflammatory Therapy with Molecular Targeting Drugs for Atherosclerotic Cardiovascular Disease: Bench to Bedside (2017)
  • Author(s): Cheng XW
  • Organizer: The 20th Annual Meeting of Yanbian Univ. Hospital
  • Invited
• [Presentation] ACDF-1 as a communicator between apoptosis and proliferation interaction during injury-related vascular repair. (2017)
  • Author(s): Cheng XW
  • Organizer: The Joint meeting of Coronary Revascularization 2017
  • Invited
• [Presentation] sFlt-1 Negative Regulates Ischemia-induced Neovascularization in Aged Mice. (2017)
  • Author(s): Cheng XW
  • Organizer: The Joint meeting of Coronary Revascularization 2017
  • Invited
• [Presentation] Exenatide Mitigated Diet induced Vascular Aging and Atherosclerotic Plaque Growth in ApoE-Deficient Mice under Chronic Stress. (2017)
  • Author(s): Yang Gaung, Yanna Lei, Aiko Inoue, limei Piao, Takeshi Sasaki, Masafumi KuzuyaXian, Xian Wu Cheng.
  • Organizer: American Heart Association 2017
  • Int'l Joint Research