Development of novel therapeutic approach for diabetic cardiomyopathy by modification of AMP deaminase activity.

• Project/Area Number: 17K09584
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Sapporo Medical University
• Principal Investigator: Tanno Masaya 札幌医科大学, 医学部, 准教授 (00398322)
• Co-Investigator(Kenkyū-buntansha): 矢野 俊之 札幌医科大学, 医学部, 講師 (40444913) ; 三浦 哲嗣 札幌医科大学, 医学部, 教授 (90199951)
• 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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 糖尿病性心筋症 / 心不全 / AMPデアミナーゼ / 拡張機能障害 / Sarcoplasmic Reticulum

Outline of Final Research Achievements

The role of AMP deaminase (AMPD) in the left ventricular diastolic dysfunction in diabetic cardiomyopathy has been examined. Activity of AMPD was upregulated in the myocardium of type 2-diabetic rats, contributing to the manifestation of latent diastolic dysfunction via depletion of adenine nucleotide pool and ATP. Furthermore, we found that the activity of AMPD is regulated by microRNA 301b-mediated translational modification of ts protein expression level. Finally, AMPD3 also elevated the level of IMP and its downstream purine metabolic pathway molecules, substrates of xanthine oxidase (XO), resulting in production of excess reactive oxygen species (ROS) via XO-mediated reaction. The increased ROS aggravated the state 3 respiration of the mitochondria and suppressed ATP production. These finding indicate that upregulation of AMPD induced left ventricular diastolic dysfunction of diabetic hearts through both excess ATP degradation and insufficient ATP production.

Academic Significance and Societal Importance of the Research Achievements

糖尿病患者の急激な増加とともに糖尿病性心筋症は増加の一途を辿る。糖尿病患者の主要な死因の一つであるが、現時点では予後を改善する特異的な治療法は無く新規治療方法の開発が急務である。糖尿病性心筋症の典型的な臨床像としては潜在的な左室拡張機能障害を有し血圧上昇に伴い心不全が顕在化するが、これまでの研究では圧負荷により顕在化する心不全の機序についての検討はほとんど無い。また、現在の心不全治療は神経体液性因子の修飾としてレニン-アンジオテンシン-交感神経系の阻害のみである。心不全の発症進展への心筋代謝障害の寄与は多く報告されており、AMPDを標的とした心筋代謝制御は有望な新規治療と考えられる。

Research Products

• [Journal Article] Translational regulation by miR-301b upregulates AMP deaminase in diabetic hearts. (2018)
  • Author(s): Tatekoshi Y, Tanno M, Kouzu H, Abe K, Miki T, Kuno A, Yano T, Ishikawa S, Ohwada W, Sato T, Niinuma T, Suzuki H, Miura T.
  • Journal Title: J Mol Cell Cardiol Volume: 119 Pages: 138-146
  • DOI: 10.1016/j.yjmcc.2018.05.003
  • Peer Reviewed
• [Presentation] Novel microRNA-mediated regulation of AMP deaminase, a key player in diabetic cardiomyopathy. (2019)
  • Author(s): Tanno M.
  • Organizer: 日本循環器学会年次学術集会
  • Invited
• [Presentation] Functional and metabolic impairments in type 2 diabetic hearts under pressure overload are improved by inhibition of xanthine oxidase. (2019)
  • Author(s): Igaki Y, Tanno M, Sato T, Yano T, Kuno A, Miura T.
  • Organizer: 日本循環器学会基礎研究フォーラム
• [Presentation] Pressure overload-induced functional and metabolic impairments in type 2 diabetic hearts are ameliorated by inhibition of xanthine oxidase (2019)
  • Author(s): Igaki Y, Tanno M, Kouzu H, Sato T, Tatekoshi Y, Yano T, Kuno A, Miki T, Miura T.
  • Organizer: ESC asia with APCS and AFC
• [Presentation] Synergetic effect of amino acid and ketone metabolism underlies empagliflozin-mediated cardioprotection in the type 2 diabetic heart. (2019)
  • Author(s): Kouzu H, Oshima H, Miki T, Kuno A, Sato T, Yano T, Tanno M, Miura T.
  • Organizer: ESC asia with APCS and AFC
• [Presentation] 糖尿病性心筋症における拡張機能障害は、キサンチンオキシダーゼ阻害により抑制される (2019)
  • Author(s): 井垣勇祐, 丹野雅也, 神津英至, 佐藤達也,三浦哲嗣
  • Organizer: 日本心筋症研究会
• [Presentation] Novel microRNA-mediated regulation of AMP deaminase, a key player in diabetic cardiomyopathy (2019)
  • Author(s): 丹野雅也
  • Organizer: 日本循環器学会学術集会
  • Invited
• [Presentation] Upregulation of AMP deaminase in the vicinity of sarcoplasmic reticulum through miRNA mediated translational regulation : a novel mechanism of diabetic cardiomyopathy (2017)
  • Author(s): Tatekoshi Y, Tanno M, Miki T, Kuno A, Yano T, Ono K, Ohwada W, Mizuno M, Nakata K, Abe K and Miura T
  • Organizer: 日本循環器学会学術集会
• [Presentation] Dysregulation of miR-301b contributes to diabetic cardiomyopathy via upregulation of AMP deaminasein the vicinity of the sarcoplasmic reticulum (2017)
  • Author(s): Tatekoshi Y, Tanno M, Miki T, Kuno A, Yano T, Ohwada W, Abe K, Igaki Y, Fujita Y and Miura T
  • Organizer: American Heart Association 2017 . Anaheim, CA, U.S.A
  • Int'l Joint Research
• [Presentation] Upregulation of AMP deaminase in the vicinity of the SR via translational regulation by miR - 301b contributes to diabetic cardiomyopathy (2017)
  • Author(s): Tatekoshi Y, Tanno M, Miki T, Kuno A, Yano T, Ohwada W, Abe K, Igaki Y, Fujita Y, Miura T.
  • Organizer: 日本心不全学会学術集会
• [Book] 今日の疾患辞典 (2019)
  • Author(s): 丹野雅也、三浦哲嗣
  • Publisher: 株式会社プレシジョン
• [Book] 医学のあゆみ (2017)
  • Author(s): 舘越勇輝、丹野雅也
  • Total Pages: 2
  • Publisher: 医歯薬出版株式会社