The role of microRNA in molecular mechanism of heart failure development

• Project/Area Number: 16K09504
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Kumamoto University
• Principal Investigator: Miyata Keishi 熊本大学, 大学院生命科学研究部(医), 特任准教授 (50398228)
• Project Period (FY): 2016-04-01 – 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 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 心不全 / 運動 / miR-221 / miR-222 / 運動負荷 / マイクロRNA

Outline of Final Research Achievements

It has been reported that miRNA is induced by exercise training. However, it is unclear whether the exercise-induced miRNAs have a cardioproctective function. We found that exercise training significantly increased the expression levels of miR-221 and miR-222 in serum and whole heart tissue compared with sedentary control mice. And pressure overload-induced cardiac stress following transverse aorta constriction (TAC) mouse model also markedly increased the expression levels of miR-221 and miR-222 in whole heart tissue compared with controls. Furthermore, cardiomyocyte-specific miR-221/222 KO mice with TAC operation were predisposed to heart failure development. Taken together, we indicated that miR-221 and miR-222 have a cardioprotective function. The study suggests that exercise-induced miR-221 and miR-222 may attenuate the development of heart failure.

Academic Significance and Societal Importance of the Research Achievements

本研究では運動によって誘導されるmiR-221及びmiR-222が心不全病態形成において心保護作用を示すこと、さらにその標的遺伝子を同定し、新たな心不全発症病態の分子機構を見出した。運動により産生・分泌されるmiR-221及びmiR-222の運動による組織部位だけでなく時間的な発現パターンを含めた分子機構が解明されれば、運動由来のmiRNAの心保護作用の観点からヒト心不全の新規予防・治療法開発に繋がる基盤研究となり大きく期待される。

Research Products

• [Int'l Joint Research] University of Utah School of Medicine(米国)
• [Journal Article] Loss of Endogenous HMGB2 Promotes Cardiac Dysfunction and Pressure Overload-Induced Heart Failure in Mice (2019)
  • Author(s): Sato M, Miyata K, Tian Z, Kadomatsu T, Ujihara Y, Morinaga J, Horiguchi H, Endo M, Zhao J, Zhu S, Sugizaki T, Igata K, Muramatsu M, Minami T, Ito T, Bianchi ME, Mohri S, Araki K, Node K, Oike Y
  • Journal Title: Circulation Journal Volume: 83 Issue: 2 Pages: 368-378
  • DOI: 10.1253/circj.CJ-18-0925
  • NAID: 130007557092
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2019-01-25
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Age-dependent increase in angiopoietin-like protein 2 accelerates skeletal muscle loss in mice. (2018)
  • Author(s): Zhao J, Tian Z, Kadomatsu T, Xie P, Miyata K, Sugizaki T, Endo M, Zhu S, Fan H, Horiguchi H, Morinaga J, Terada K, Yoshizawa T, Yamagata K, Oike Y.
  • Journal Title: J Biol Chem Volume: 293 Issue: 5 Pages: 1596-1609
  • DOI: 10.1074/jbc.m117.814996
  • Peer Reviewed / Open Access
• [Journal Article] ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism. (2016)
  • Author(s): Tian Z, Miyata K, Kadomatsu T, Horiguchi H, Fukushima H, Tohyama S, Ujihara Y, Okumura T, Yamaguchi S, Zhao J, Endo M, Morinaga J, Sato M, Sugizaki T, Zhu S, Terada K, Sakaguchi H, Komohara Y, Takeya M, Takeda N, Araki K, Manabe I, Fukuda K, Otsu K, Wada J, Murohara T, Mohri S, Yamashita JK, Sano M, Oike Y.
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 13016-13016
  • DOI: 10.1038/ncomms13016
  • NAID: 120006345014
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Endurance exercise-induced miR221/222 promotes cardioprotection via ANGPTL2 suppression. (2017)
  • Author(s): Keishi Miyata
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県金沢市