Role of aging regulatory protein WRN in cardiac fibrosis

• 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. 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
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• 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 / 老化 / 線維化 / 循環器・高血圧 / 糖尿病

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.

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。

Research Products

• [Journal Article] Werner syndrome gene mutation is responsible for cardiac aging with transition from diastolic to systolic LV dysfunction. (2018)
  • Author(s): Kamihara T, Bando YK, Nishimura K, Murohara T
  • Journal Title: EUROPEAN HEART JOURNAL Volume: 39 Issue: suppl_1 Pages: 1398-1398
  • DOI: 10.1093/eurheartj/ehy566.p6548
  • Peer Reviewed
• [Presentation] Werner gene is responsible for cardiac aging with disability of autophagy (2019)
  • Author(s): Kamihara T, Bando YK, Nishimura K, Murohara T
  • Organizer: 第83回日本循環器学会学術総会
• [Presentation] Werner syndrome gene mutation is responsible for cardiac aging with transition from diastolic to systolic LV dysfunction. (2018)
  • Author(s): Kamihara T, Bando YK, Nishimura K, Murohara T
  • Organizer: Congress of the European-Society-of-Cardiology (ESC)2018
  • Int'l Joint Research
• [Presentation] Werner syndrome gene mutation is responsible for cardiac aging with transition from diastolic to systolic LV dysfunction (2018)
  • Author(s): Kamihara T, Bando YK, Nishimura K, Murohara T
  • Organizer: International Meeting on RECQ helicases and related diseases 2018
  • Int'l Joint Research
• [Presentation] Werner syndrome gene mutation is responsible for cardiac aging with transition from diastolic to systolic LV dysfunction (2018)
  • Author(s): Takahiro Kamihara, Yasuko K. Bando, Haruya Kawase, Kazuyuki Nishimura, Remina Yasheng, Toyoaki Murohara
  • Organizer: International Meeting on RECQ Helicases and Related Diseases(RECQ2018)
  • Int'l Joint Research
• [Presentation] WRN-KD mutation was found to link to the regulation of cardiac hypertrophy via PKA/ERK/p53 axis independently of glucose metabolism (2018)
  • Author(s): Takahiro Kamihara, Yasuko K. Bando, Haruya Kawase, Kazuyuki Nishimura, Remina Yasheng, Toyoaki Murohara
  • Organizer: 第1回日本循環器学会基礎研究フォーラム
• [Presentation] Aging-accelerating molecule Werner protein augments myocardial fibrosis in a teneicin-C-independent fashion. (2017)
  • Author(s): Kazuyuki Nishimura, Yasuko K. Bando, Haruya Kawase, Kyoko Imanaka-Yoshida, Toyoaki Murohara
  • Organizer: 第81回日本循環器学会総会
  • Place of Presentation: 金沢都ホテル 石川県 金沢市
• [Presentation] Mouse Model Of Werner Syndrome Exhibits Cardiac Remodeling And Resistance To Diabetes Due To Altered Glucagon Response. (2016)
  • Author(s): Yasuko K. Bando, Haruya Kawase, Kazuyuki Nishimura, Toyoaki Murohara,
  • Organizer: Scientific Sessions 2016, American heart Association
  • Place of Presentation: Ernest N. Morial Convention Center, New Orleans USA