Developing novel heart failure therapy targeting DEAD-box RNA helicase

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08488
• 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: The University of Tokyo
• Principal Investigator: Higashikuni Yasutomi 東京大学, 医学部附属病院, 助教 (10586481)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 心不全 / RNA代謝 / RNAヘリカーゼ / 炎症 / DNA損傷 / ミトコンドリア機能障害 / 遺伝子治療

Outline of Final Research Achievements

RNA metabolism is a fundamental mechanism that controls protein synthesis. Changes in RNA metabolism have been implicated in the pathogenesis of heart failure. However, their mechanisms remain largely unknown. Ddx41 is an RNA helicase that binds to RNA and regulates RNA metabolism. This study sought to elucidate the role and mechanism of Ddx41-mediated RNA metabolism in the pathophysiology of heart failure. Ddx41 was upregulated in human failing hearts. Mice with cardiomyocyte-specific overexpression of Ddx41 showed worse survival rate and cardiac remodeling during pressure overload or after myocardial infarction than wild-type mice. We found that Ddx41 binds to mRNAs and proteins related to inflammatory responses, which leads to DNA damage and mitochondrial dysfunction in cardiomyocytes. Inhibition of Ddx41 protected cardiomyocytes against DNA damage and mitochondrial dysfunction. Collectively, our results suggest that Ddx41 might be a promising therapeutic target for heart failure.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

予後不良の病態である心不全は超高齢化社会である我が国において急増しており、新規治療法の開発が急務である。本研究により、RNA代謝の担い手であるRNAヘリカーゼDdx41が心不全の病態に深く寄与することを解明した。心不全発症におけるRNA代謝の変容の重要性とその治療的介入点が明らかとなった。
学術的には、Ddx41が炎症関連因子のRNA及び蛋白質と結合し、DNA損傷とミトコンドリア機能障害を誘導することを解明した。心不全発症におけるRNA代謝と炎症誘導機構をつなぐ機序の一端が明らかとなった。Ddx41はがん等の疾患の発症にも寄与しており、本研究成果は心不全以外の疾患の病態生理の解明につながる。