Mechanisms underlying regulation of AMP deaminase activity and its involvement in the pathophysiology of diabetic cardiomyopathy

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08110
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Tanno Masaya 札幌医科大学, 保健医療学部, 教授 (00398322)
• Co-Investigator(Kenkyū-buntansha): 久野 篤史 札幌医科大学, 医学部, 教授 (30468079) ; 矢野 俊之 札幌医科大学, 医学部, 講師 (40444913)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 糖尿病性心筋症 / AMPデミナーゼ / ミトコンドリア小胞体近接領域

Outline of Final Research Achievements

We investigated roles of AMP deaminase (AMPD) localized in the mitochondria-associated ER membrane (MAM) in the pathophysiology of diabetic cariomyopathy. By analyzing proteins contained in the MAM fraction in the left ventricular myocardium, AMPD was found to be localized in the MAM area more abundantly in type 2-diabetic rats with diabetic cardiomyopathy than in the MAM area of non-diabetic control rats. Furthermore, we found that AMPD overexpressed in H9c2 cells and primary cardiomyocytes reside in the MAM area, resulting in promoted MAM formation, increased mitochondrial Ca2+ level, decreased mitochondrial calcium retention capacity, augmented oxidative stress, all of which contributed to the reduction of mitochondrial membrane potential. These findings indicate that AMPD excessively localized in the MAM area is associated with the pathophysiology of diabetic cardiomyopathy.

Free Research Field

心不全

Academic Significance and Societal Importance of the Research Achievements

糖尿病性心筋症は、発症早期には左室拡張機能障害を呈し、左室収縮能の維持された心不全（HF-pEF）の主要な原因の一つである。その後、左室収縮能が低下した心不全(HF-rEF)へと進行する。HFpEFを呈する本症はその患者数の増加にも関わらず、現時点では根本的な治療は無く、破綻した血行動態の是正や過剰に貯留した体液の軽減を図る対症療法が中心となる。必然的に改善は一時的であり、再増悪を繰り返すことが多い。本研究で見出された、糖尿病性心筋症におけるAMPDによるMAMの過形成が関連するミトコンドリアのCa2+の過負荷は、糖尿病性心筋症における新たな治療標的になり得ると考えられる。