Role of aging regulatory protein WRN in cardiac fibrosis

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09496
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Nagoya University
• Principal Investigator: Bando Yasuko K. (暮石泰子) 名古屋大学, 医学部附属病院, 講師 (60452190)
• Co-Investigator(Kenkyū-buntansha): 吉田 恭子 (今中恭子) 三重大学, 医学系研究科, 准教授 (00242967) ; 室原 豊明 名古屋大学, 医学系研究科, 教授 (90299503)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: ウェルナー症候群 / 心臓拡張不全 / 心不全 / オートファジー / 酸化ストレス

Outline of Final Research Achievements

[Background/Introduction] Aging is known to be one of the primary causes of heart failure. Werner syndrome is one of the aging disorder that caused by dysfunction of DNA helicase-regulatory protein (WRN). [Results] WRN-K577M exhibited diffuse left-ventricular (LV) hypertrophy, enhanced fibrosis, and diastolic LV
dysfunction with preserved systolic ejection fraction. DNA microarray analysis of WRN-K577M heart revealed that the 253 genes were upregulated including hypertrophy, fibrosis, inflammation, and oxidative stress. Notably, p62 and LC3-II/I were increased in myocardium of WRN-K577M. Blockade of the lysosomal fusion into autophagosome by systemic treatment with chloroquine reduced LC3-II/I ratio.[Conclusion(s)] In WRN-mutant progeria model, off-rate disorder of cardiac autophagy is, at least in part, the cause of increase in oxidative stress and inflammation in heart leading to HFpEF.

Free Research Field

循環器内科

Academic Significance and Societal Importance of the Research Achievements

超高齢化社会に突入し、高齢者心不全患者数の増加とその予防は喫緊の課題である。本研究の成果は、高齢者に最も多いと言われる拡張不全型心不全の予防介入として、オートファジー活性調整が有用である可能性を示唆している。