Elucidation of molecular mechanism and treatment application of heart failure by transcription factor and DNA damage response factor

• Project/Area Number: 15K09145
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Jichi Medical University
• Principal Investigator: Aizawa Kenichi 自治医科大学, 医学部, 准教授 (70436484)
• Co-Investigator(Kenkyū-buntansha): 永井 良三 自治医科大学, 医学部, 学長 (60207975)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 循環器内科学 / 分子心臓学

Outline of Final Research Achievements

The heart causes myocardial remodeling as an adaptation to load. Although many cardiac hypertrophy inducers are already known, the mechanism of adaptive failure leading to heart failure has not been fully elucidated. We have previously shown that the cardiac stromal cell transcription factor KLF5 is important for load adaptation, and that acetylation of KLF5 is involved in cell proliferation in vitro. In this study, we focused on the acetylation of KLF5 molecule and DNA repair factor (ATM etc.) and clarified the role in adaptation and failure of the heart at individual level. It has been revealed that KLF5 non-acetylated mutant mice and ATM deficient mice produce abnormalities in cardiac development and hypertrophy. Furthermore, we isolated factors that interact with them and identified new therapeutic targets.

Academic Significance and Societal Importance of the Research Achievements

心不全は近年増加しつつある高血圧性心疾患、虚血性心疾患の最終病態であり、この問題を解決することは臨床的のみならず社会的にも重要である。これまでの心不全の薬物治療は心不全状態で活性化される細胞外の神経・体液性因子を標的としたものであった。本研究は動脈硬化、心肥大が転写因子とその相互作用因子により制御されることを明らかにし、その鍵分子である転写因子KLF5とDNA損傷応答機構が、心肥大・心不全の発症機序の鍵となる可能性を示した。すなわち、本研究は心筋リモデリングにおける病態生理の解明、ひいては新規治療薬開発につながると期待される。

Research Products

• [Journal Article] 循環器臨床におけるプロテオミクスの現状と将来展望 (2018)
  • Author(s): 相澤健一
  • Journal Title: Precision Medicine Volume: 1 Pages: 136-139
• [Journal Article] Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity (2016)
  • Author(s): Zhan H, Aizawa K, Sun JQ, Tomida S, Otsu K, Conway S, McKinnon P, Manabe I, Komuro I, Miyagawa K, Nagai R, Suzuki T
  • Journal Title: Cardiovasc. Res. Volume: 110 Issue: 1 Pages: 85-95
  • DOI: 10.1093/cvr/cvw032
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant