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

2019 Fiscal Year Final Research Report

• 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
• Keywords: 糖尿病性心筋症 / 心不全 / AMPデアミナーゼ / 拡張機能障害

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.

Free Research Field

心不全

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。