Development of functional aptamers as a comprehensive therapeutic agent for cardiovascular disease

• Project/Area Number: 17K08968
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Showa University (2019); Kurume University (2017-2018)
• Principal Investigator: YAMAGISHI SHO-ICHI 昭和大学, 医学部, 教授 (40281026)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: DNAアプタマー / グリセルアルデヒド由来ピリジニウム / 終末糖化産物 / GLAPアプタマー / AGEsアプタマー / PEDF受容体 / アプタマー / PEDF / ラミニン受容体

Outline of Final Research Achievements

Advanced glycation end products (AGEs) are proteins formed by non-enzymatic glycation of free amino groups by sugars and aldehydes, and accumulation of AGEs is associated with the development and progression of various age-related diseases. We found that glyceraldehyde-derived pyridinium (GLAP) and fructose-derived AGEs induced inflammatory responses in vascular endothelial cells and renal proximal tubular epithelial cells through generation of oxidative stress. In addition, we developed DNA aptamers that can bind to GLAP or AGEs, and demonstrated that these aptamers inhibited inflammatory responses induced by GLAP and AGEs.

Academic Significance and Societal Importance of the Research Achievements

人口が高齢化しつつある我が国において、老年病への対策は重要な問題となっている。DNAアプタマーは、抗体医薬品に比ベて安価で、大量に調整もできることから、次世代のバイオ医薬品として注目を集めている。本研究によって、グリセルアルデヒド由来ピリジニウムやAGEsと結合してその機能を阻害するDNAアプタマーの有用性が示され、包括的に老年病を制御する治療法の開発につながると予想される。

Research Products

• [Journal Article] Glyceraldehyde-Derived Pyridinium Evokes Renal Tubular Cell Damage via RAGE Interaction. (2020)
  • Author(s): Ami Sotokawauchi, Nobutaka Nakamura, Takanori Matsui, Yuichiro Higashimoto, Sho-ichi Yamagishi
  • Journal Title: Int J Mol Sci. Volume: 21 Issue: 7 Pages: 2604-2611
  • DOI: 10.3390/ijms21072604
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fructose causes endothelial cell damage via activation of advanced glycation end products-receptor system. (2019)
  • Author(s): Sotokawauchi A, Matsui T, Higashimoto Y, Yamagishi SI.
  • Journal Title: Diab. Vasc. Dis. Res. Volume: 16 Issue: 6 Pages: 556-561
  • DOI: 10.1177/1479164119866390
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Therapeutic potential of pigment epithelium-derived factor in cancer. (2019)
  • Author(s): Yamagishi SI, Koga Y, Sotokawauchi A, Hashizume N, Fukahori S, Matsui T, Yagi M
  • Journal Title: Curr Pharm Des. Volume: 印刷中 Issue: 3 Pages: 313-324
  • DOI: 10.2174/1381612825666190319112106
  • Peer Reviewed
• [Journal Article] Pathological role of advanced glycation end products (AGEs) and their receptor axis in atrial fibrillation (2019)
  • Author(s): Yamagishi Sho-ichi、Sotokawauchi Ami、Matsui Takanori
  • Journal Title: Mini-Reviews in Medicinal Chemistry Volume: 19 Issue: 13 Pages: 1040-1048
  • DOI: 10.2174/1389557519666190311140737
  • Peer Reviewed
• [Journal Article] Concerns about clinical efficacy and safety of warfarin in diabetic patients with atrial fibrillation (2019)
  • Author(s): Yamagishi Sho-ichi
  • Journal Title: Cardiovascular Diabetology Volume: 18 Issue: 1
  • DOI: 10.1186/s12933-019-0818-0
  • Peer Reviewed
• [Journal Article] Serum Levels of Protein-Bound Methylglyoxal-Derived Hydroimidazolone-1 are Independently Correlated with Asymmetric Dimethylarginine (2019)
  • Author(s): Tahara Nobuhiro、Kojima Ruchia、Yoshida Risa、Bekki Munehisa、Sugiyama Yoichi、Tahara Atsuko、Maeda Shoko、Honda Akihiro、Igata Sachiyo、Nakamura Tomohisa、Sun Jiahui、Matsui Takanori、Fukumoto Yoshihiro、Matsui Toshiro、Yamagishi Sho-Ichi
  • Journal Title: Rejuvenation Research Volume: 印刷中 Issue: 5 Pages: 431-438
  • DOI: 10.1089/rej.2018.2152
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Role of Hyperglycemia-Induced Advanced Glycation End Product (AGE) Accumulation in Atherosclerosis (2018)
  • Author(s): Yamagishi Sho-ichi、Matsui Takanori
  • Journal Title: Annals of Vascular Diseases Volume: 11 Issue: 3 Pages: 253-258
  • DOI: 10.3400/avd.ra.18-00070
  • NAID: 130007487741
  • ISSN: 1881-641X, 1881-6428
  • Year and Date: 2018-09-25
  • Peer Reviewed
• [Journal Article] Are Finger Skin Fluorophores Other Than Advanced Glycation End Products (AGEs) Associated With Impaired Musculoskeletal Properties? (2018)
  • Author(s): Yamagishi Sho-ichi
  • Journal Title: The Journals of Gerontology: Series A Volume: 印刷中
  • DOI: 10.1093/gerona/gly280
  • Peer Reviewed
• [Journal Article] Aqueous Extract of Glucoraphanin-Rich Broccoli Sprouts Inhibits Formation of Advanced Glycation End Products and Attenuates Inflammatory Reactions in Endothelial Cells (2018)
  • Author(s): Sotokawauchi Ami、Ishibashi Yuji、Matsui Takanori、Yamagishi Sho-ichi
  • Journal Title: Evidence-Based Complementary and Alternative Medicine Volume: 2018 Issue: 1 Pages: 1-6
  • DOI: 10.1155/2018/9823141
  • Peer Reviewed
• [Journal Article] Therapeutic Potential of DNA-aptamers Raised Against AGE-RAGE Axis in Diabetes-related Complications (2018)
  • Author(s): Yamagishi Sho-ichi、Matsui Takanori
  • Journal Title: Current Pharmaceutical Design Volume: 24 Issue: 24 Pages: 2802-2809
  • DOI: 10.2174/1381612824666180829110124
  • Peer Reviewed
• [Journal Article] Sex disparity in cardiovascular mortality rates associated with diabetes (2018)
  • Author(s): Yamagishi Sho-ichi
  • Journal Title: Diabetes/Metabolism Research and Reviews Volume: 34 Issue: 8
  • DOI: 10.1002/dmrr.3059
  • Peer Reviewed
• [Journal Article] Advanced glycation end products evoke inflammatory reactions in proximal tubular cells via autocrine production of dipeptidyl peptidase-4 (2018)
  • Author(s): Kaifu Kumiko、Ueda Seiji、Nakamura Nobutaka、Matsui Takanori、Yamada-Obara Nana、Ando Ryotaro、Kaida Yusuke、Nakata Masami、Matsukuma-Toyonaga Maki、Higashimoto Yuichiro、Fukami Kei、Suzuki Yusuke、Okuda Seiya、Yamagishi Sho-ichi
  • Journal Title: Microvascular Research Volume: 120 Pages: 90-93
  • DOI: 10.1016/j.mvr.2018.07.004
  • Peer Reviewed / Open Access
• [Journal Article] Clinical markers associated with glycaemic response to dipeptidyl peptidase-4 inhibitor therapy (2018)
  • Author(s): Yamagishi Sho-ichi
  • Journal Title: Diabetes/Metabolism Research and Reviews Volume: 34 Issue: 7
  • DOI: 10.1002/dmrr.3024
  • Peer Reviewed
• [Journal Article] Association of skin autofluorescence with plaque vulnerability evaluated by optical coherence tomography in patients with cardiovascular disease (2018)
  • Author(s): Fujino Yusuke、Attizzani Guilherme F.、Tahara Satoko、Wang Wei、Takagi Kensuke、Naganuma Toru、Yabushita Hiroto、Tanaka Kentaro、Sato Tomohiko、Watanabe Yusuke、Mitomo Satoru、Kurita Naoyuki、Ishiguro Hisaaki、Nakamura Shotaro、Hozawa Koji、Bezerra Hiram G.、Yamagishi Sho-ichi、Nakamura Sunao
  • Journal Title: Atherosclerosis Volume: 274 Pages: 47-53
  • DOI: 10.1016/j.atherosclerosis.2018.03.001
  • Peer Reviewed
• [Journal Article] Endothelial dysfunction as a common soil of lower urinary tract symptoms and cardiovascular disease (2018)
  • Author(s): Yamagishi Sho-ichi
  • Journal Title: International Journal of Cardiology Volume: 261 Pages: 209-210
  • DOI: 10.1016/j.ijcard.2018.03.033
  • Peer Reviewed
• [Journal Article] Role of Ligands of Receptor for Advanced Glycation End Products (RAGE) in Peripheral Artery Disease (2018)
  • Author(s): Yamagishi Sho-ichi、Matsui Takanori
  • Journal Title: Rejuvenation Research Volume: 21 Issue: 5 Pages: 456-463
  • DOI: 10.1089/rej.2017.2025
  • Peer Reviewed
• [Presentation] フルクトース由来終末糖化産物のアプタマーは、フルクトースが引き起こす内皮細胞障害を抑制する (2019)
  • Author(s): 外川内亜美、松井孝憲、東元祐一郎、山岸昌一
  • Organizer: 第42回日本分子生物学会
• [Presentation] 終末糖化産物受容体(RAGE)アプタマーは動物モデル糖尿病腎症の発症・増悪,悪性黒色腫の増殖・転移を抑制する (2018)
  • Author(s): 松井孝憲, 中村信孝, 東元祐一郎, 山岸昌一
  • Organizer: 日本核酸医薬学会第4回年会
• [Presentation] 終末糖化産物受容体(RAGE)アプタマーはラットの糖尿病腎症の発症と進展を抑制する (2018)
  • Author(s): 松井孝憲, 山岸昌一
  • Organizer: 第61回日本腎臓学会
• [Presentation] カナグリフロジンはヒト近位尿細管細胞におけるCarboxymethyl Lysine産生を抑制する (2018)
  • Author(s): 児玉豪, 伊藤佐久耶, 甲斐田裕介, 甲斐友宝, 松井孝憲, 山岸昌一, 深水圭
  • Organizer: 第61回日本腎臓学会
• [Presentation] トホグリフロジンは尿細管保護効果により2型糖尿病マウスの腎障害を改善する (2018)
  • Author(s): 松井 孝憲、石橋裕二、山岸 昌一
  • Organizer: 第61回日本糖尿病学会
• [Presentation] 終末糖化産物受容体(RAGE)阻害アプタマーは、ヌードマウスにおいて悪性メラノーマの増殖と転移を抑える (2018)
  • Author(s): 外川内亜美、中村信孝、松井 孝憲、山岸 昌一
  • Organizer: 第61回日本糖尿病学会
• [Presentation] 終末糖化産物受容体(RAGE)のアプタマーは動物の糖尿病腎症の発症・増悪と悪性黒色腫の増殖・転移を阻害する (2018)
  • Author(s): 松井孝憲,中村信孝, 東元祐一郎, 山岸昌一
  • Organizer: 第41回日本分子生物学会