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

• Project/Area Number: 15H04802
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General internal medicine(including psychosomatic medicine)
• Research Institution: Nagoya University
• Principal Investigator: Cheng XianWU 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
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2017: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
• 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 / ストレス

Outline of Final Research Achievements

Exposure to psychosocial stress is a risk factor for cardiovascular disease. Here, we have used dipeptidyl peptidase-4 (DPP4)-deficient mice and its inhibitor as well as glucagon-like peptide-1 (GLP-1) receptor agonist to explore the role of DPP4/GLP-1 axis in ischemia-induced neovascularization and diet-induced atherosclerosis. We demonstrated that stress impaired the recovery of the ischemic/normal blood-flow ratio throughout the follow-up period and capillary formation; and these changes DPP4 inhibition and GLP-1R activation improved these changes; these benefits were abrogated by adiponectin blocking and genetic depletion. Similarly, chronic stress accelerated diet-induced atherosclerotic lesion formation; and this effect was reversed by DPP4 inhibition. Our findings suggest that CatK might be a new therapeutic target for the chronic psychological stress-related neovascularization and cardiovascular diseases.

Research Products

• [Journal Article] Cathepsin K activity controls cardiotoxin-induced skeletal muscle repair in mice. (2018)
  • 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: J Cachexia Sarcopenia Muscle. Volume: 9 Issue: 1 Pages: 160-175
  • DOI: 10.1002/jcsm.12248
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
  • NAID: 130006434128
• [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 Issue: 3 Pages: 287-300
  • DOI: 10.14336/ad.2016.0920
  • 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 Issue: 7 Pages: e0180207-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 Guang、Lei Yanna、Inoue Aiko、Piao Limei、Hu Lina、Jiang Haiying、Sasaki Takeshi、Wu Hongxian、Xu Wenhu、Yu Chenglin、Zhao Guangxian、Ogasawara Shinyu、Okumura Kenji、Kuzuya Masafumi、Cheng Xian-Wu
  • Journal Title: Atherosclerosis Volume: 264 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: J Am Heart Assoc. Volume: 6 Issue: 7
  • 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 Yanna、Yang Guang、Hu Lina、Piao Limei、Inoue Aiko、Jiang Haiying、Sasaki Takeshi、Zhao Guangxian、Yisireyili Maimaiti、Yu Chenglin、Xu Wenhu、Takeshita Kyosuke、Okumura Kenji、Kuzuya Masafumi、Cheng Xian Wu
  • Journal Title: International Journal of Cardiology Volume: 243 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 Issue: 10
  • DOI: 10.1161/jaha.117.006421
  • 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. (2016)
  • 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: - Issue: 3 Pages: 370-385
  • DOI: 10.1002/jcsm.12166
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The Soluble VEGF Receptor sFlt-1 Contributes to Impaired Neovascularization in Aged Mice. (2016)
  • Author(s): Zhao G, Cheng XW, Piao L, Hu L, Lei Y, Inoue A, Yang G, Ogasawara S, Wu H, Hao CN, Okumura K, Kuzuya M.
  • Journal Title: Aging and Disease. Volume: ‐
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dipeptidyl peptidase- IV inhibitor alogliptin improves stress-induced insulin resistance and prothrombotic state in a murine model. (2016)
  • Author(s): Yisireyili M, Takeshita K, Hayashi M, Wu H, Uchida Y, Yamamoto K, Kikuchi R, Hao CN, Nakayama T, Cheng XW, Matsushita T, Nakamura S, Murohara T.
  • Journal Title: Psychoneuroendocrinology. Volume: 73 Pages: 186-195
  • Peer Reviewed / Open Access
• [Journal Article] Elucidating the pathophysiological significance of circulating omentin levels: Is higher better? (2016)
  • Author(s): Cheng XW.
  • Journal Title: Atherosclerosis. Volume: 251 Pages: 522-524
  • DOI: 10.1016/j.atherosclerosis.2016.06.042
  • Peer Reviewed / Open Access
• [Journal Article] 虚血成心疾患UP DATE冠動脈疾患基礎研究の進歩 冠動脈硬化の新しい分子機序-炎症・免疫からみた最新の知見 (2016)
  • Author(s): 成憲武、井上愛子
  • Journal Title: 医学のあゆみ Volume: 259(6) Pages: 590-596
  • Peer Reviewed
• [Journal Article] Increased expression and activation of cathepsin K in human osteoarthritic cartilage and synovial tissues. (2016)
  • Author(s): Kozawa E, Cheng XW, Urakawa H, Arai E, Yamada Y, Kitamura S, Sato K, Kuzuya M, Ishiguro N, Nishida Y.
  • Journal Title: J Orthop Res. Volume: 34(1): Issue: 1 Pages: 127-34
  • DOI: 10.1002/jor.23005
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cathepsin S Activity Controls Ischemia-Induced Neovascularization in Mice (2015)
  • Author(s): Li X, Cheng XW, Hu L, Wu HX, Hao CH, Shi GP, Jiang H, Zhu E, Inoue A, Huang Z, Sasaki T, Takeshita K, Okumura K, Murohara T, Kuzuya M
  • Journal Title: International Journal of Cardiology Volume: 183 Pages: 198-208
  • DOI: 10.1016/j.ijcard.2015.01.058
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 特集 高齢者医療におけるサルコペニア・フレイル対策 ３．サルコペニア・フレイルのバイオマーカー (2015)
  • Author(s): 井上愛子、成憲武、葛谷雅文．
  • Journal Title: 医薬ジャーナル Volume: 51(9) Pages: 67-71
• [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] Role of Cysteinyl Cathepsins in Atherosclerosis-Based Cardiovascular Disease: Focus on Novel Biology and Mechanisms. (2017)
  • Author(s): 成 憲武
  • Organizer: Kyudai Oral Bioscience 2017 (KOB2017).
  • Place of Presentation: 九州大学コラボレーションステーション（福岡県博多市）
  • Year and Date: 2017-02-11
  • Int'l Joint Research / Invited
• [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
• [Presentation] DPP4 Regulates Hematopoietic Stem Cell Activation in Response to Chronic stress. (2016)
  • Author(s): Cheng XW.
  • Organizer: Joint meeting of Coronary Revascularization (JCR2016)
  • Place of Presentation: 釜山(韓国)
  • Year and Date: 2016-12-09
  • Invited
• [Presentation] Prevention of muscle wasting with aging in SAMP10 mice by a combination of exercise and intrabone young bone marrow injection (2016)
  • Author(s): Cheng XW, Inoue A, Hu L, Piao L, Kuzuya M.
  • Organizer: 2nd Asian Conference for Frailty and Sarcopenia
  • Place of Presentation: 今池ガスビル(愛知県名古屋市）
  • Year and Date: 2016-11-04
  • Int'l Joint Research
• [Presentation] Dipeptidyl Peptidase-4 (DPP4) Inhibition for the Treatment of Neovascularization: New and Promising, or Not? (2016)
  • Author(s): Cheng XW.
  • Organizer: Kyung Hee University Hospital Cardiology Meeting
  • Place of Presentation: ソウル(韓国j)
  • Year and Date: 2016-09-29
  • Invited
• [Presentation] Cathepsin S Activity Controls Injury-Related Vascular Repair in Mice (2016)
  • Author(s): Cheng XW, Wu HX, Hu L, Takeshita K, Du QN, Piao L, Kuzuya M, Murohara T.
  • Organizer: 第48回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-07-14
• [Presentation] Dipeptidyl Peptidase-4 Inhibition Suppressed Atherosclerotic Lesion Formation in ApoE Deficient Mice. (Running title: Pitavastatin inhibits TLR expression and angiogenesis) (2016)
  • Author(s): Lei Y, Cheng XW, Piao L, Hu L, Inoue A, Kuzuya M.
  • Organizer: 第48回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-07-14
• [Presentation] Dipeptidyl Peptidase-4 Inhibition Suppressed Atherosclerotic Lesion Formation in ApoE-Deficient Mice (2016)
  • Author(s): 成 憲武, 朴 麗梅, 類 延娜, 胡 麗娜, 葛谷 雅文
  • Organizer: 第58回日本老年医学会学術集会（ノバルティス老化および老年医学研究基金2014年度受賞講演）
  • Place of Presentation: 石川県立音楽堂ほか(石川県金沢市）
  • Year and Date: 2016-06-08
• [Presentation] Cathepsin S Activity Controls Injury-Related Vascular Repair in Mice via and PI3K-Akt/p-HDAC6-Dependent Signaling Pathway. (2016)
  • Author(s): 呉 宏憲、成 憲武、胡 麗娜、井上 愛子、竹下 亨典、史 国平、室原 豊明．
  • Organizer: 第80回日本循環器学会・学術集会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2016-03-18
• [Presentation] Impaired Cross-Activation of β3 Integrin and VEGFR-2 on ECs and EPCs with Aging Decreases Angiogenesis in Response to Hypoxia. (2015)
  • Author(s): 成 憲武．
  • Organizer: 第47回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2015-07-09
• [Presentation] Cathepsin S Activity Controls Ischemia-Induced Neovascularization in Mice. (2015)
  • Author(s): 胡 麗娜、成 憲武、李 香、呉 宏憲、井上 愛子、佐々木 健、室原 豊明、葛谷 雅文．
  • Organizer: 第47回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2015-07-09
• [Presentation] Cathepsin K-Mediated Notch 1 Activation Contributes to lschemiainduced Neovascularisation in Aged Mice. (2015)
  • Author(s): 成 憲武、趙 光賢、朴 麗梅、姜 海英、胡 麗娜、佐々木 健、室原 豊明、葛谷 雅文．
  • Organizer: 第47回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2015-07-09