2022 Fiscal Year Final Research Report

Resarch on prevention of cyclophosphamide cardiotocity by removing acrolein

Research Project

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Project/Area Number	20K08232
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 52050:Embryonic medicine and pediatrics-related
Research Institution	Kagoshima University
Principal Investigator	Nishikawa Takuro 鹿児島大学, 医歯学域医学系, 准教授 (90535725)
Co-Investigator(Kenkyū-buntansha)	河野嘉文鹿児島大学, 医歯学域医学系, 教授 (20260680) 児玉祐一鹿児島大学, 医歯学域鹿児島大学病院, 講師 (20535695) 宮原恵弥子鹿児島大学, 医歯学総合研究科, 客員研究員 (20778427) 岡本康裕鹿児島大学, 医歯学域医学系, 教授 (30398002)
Project Period (FY)	2020-04-01 – 2023-03-31
Keywords	心筋障害 / シクロフォスファミド / 造血細胞移植 / アクロレイン / マイクロアレイ解析
Outline of Final Research Achievements	To elucidate acute structural changes in myocardial cells and pathways leading to myocardial damage in mice treated with high-dose CY, we performed detailed pathological analyses of myocardial tissue obtained from C57BL/6J mice that received high-dose CY. In addition, we analyzed the genome-wide cardiomyocyte expression profile of mice that received high-dose CY. Treatment with CY caused marked ultrastructural aberrations with electron microscopy. Expansion of the transverse tubule and sarcoplasmic reticulum, turbulence of myocardial fiber travel, and low contractile protein density in cardiomyocytes were observed. High-dose CY treatment changed cardiomyocyte expression of 1,210 genes associated with cell-cell junctions, inflammatory responses, cardiomyopathy, and cardiac muscle function, as detected by microarray analysis. Our results of gene expression profiles suggest that cardiotoxicity induced by CY is associated with a disruption of the Ca2+ signaling pathway.
Free Research Field	小児科学
Academic Significance and Societal Importance of the Research Achievements	造血細胞移植医療で欠かせない大量シクロフォスファミド（CY）療法であるが、その重大な副作用として致死性の心毒性が挙げられる。しかし、CY心毒性の機序や予防手段などはまだ解明されていない。今回のマウス実験、研究成果により、大量CY投与によりカルシウムイオンの恒常性破綻が心筋収縮能の低下につながっていることが推測された。これは今までの報告にないCY心筋障害の機序であった。そして、カルシウムイオンの恒常性を保つこともCY心筋障害の予防につながる可能性が見いだされた。