Elucidation of molecular basis of heart failure development from the point of view of epigenome regulation.

• Project/Area Number: 16K15445
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Kumamoto University
• Principal Investigator: Oike Yuichi 熊本大学, 大学院生命科学研究部(医), 教授 (90312321)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 心不全 / ノンコーディングRNA / non-coding RNA

Outline of Final Research Achievements

We investigated molecular mechanisms of cardiac specific long non-coding RNA X (CSLR-X), which was identified among embryonic cardiac specific expressed-clones of long non-coding RNA with gene trap approach, under heart failure development and progression. To assess whether cardiac phenotypes observed in CSLR-X KO (KO) mice were attributable to loss of cardiomyocyte-derived CSLR-X, we have established cardiac specific overexpressed CSLR-X Tg (Tg) mice and cardiac specific CSLR-X conditional KO (CKO) mice. Tg and CKO mice showed no differences of cardiac morphology and cardiac function compared with their littermate wild-type mice, respectively. And to identify mechanisms underlying the effect of CSLR-X on cardiac function, we performed the proteome analysis of whole heart tissues using KO, CAG-CSLR-X Tg and wild-type mice and identified several candidate proteins.

Academic Significance and Societal Importance of the Research Achievements

lncRNAは存在が認識され間もないため、機能解析は主に培養細胞を用いて行われており、生体での機能解明の報告は数少ない。さらに、細胞質lncRNAの作用機構は核内lncRNAよりも、作用機構が十分に明らかになっていない。本研究によって得られる成果により、心肥大・心不全の病態形成に関わる世界初の細胞質lncRNAの作用機構が明らかとなり、予後不良の疾患である心不全へのlncRNAという新たな観点からの新規治療法開発の基盤研究としての可能性が期待される。

Research Products

• [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 ― A New Causal Player in Accelerating Heart Disease Development in the Aging ― (2017)
  • Author(s): Oike Y, Tian Z, Miyata K, Morinaga J, Endo M, Kadomatsu T.
  • Journal Title: Circulation Journal Volume: 81 Issue: 10 Pages: 1379-1385
  • DOI: 10.1253/circj.CJ-17-0854
  • NAID: 130006099927
  • ISSN: 1346-9843, 1347-4820
  • 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] 心血管疾患と代謝・生活習慣病の共通分子病態におけるANGPTL2の役割 (2018)
  • Author(s): 尾池 雄一
  • Organizer: 第47回日本心脈管作動物質学会
  • Invited
• [Presentation] 肥満症と心血管疾患の共通分子基盤 (2017)
  • Author(s): 尾池 雄一
  • Organizer: 第38回日本肥満学会 シンポジウム12 メタボリックシンドロームと心血管病～新たな分子病態基盤と治療ターゲットの探索～
  • Invited
• [Presentation] アンジオポエチン様因子2と心血管疾患 (2016)
  • Author(s): 尾池雄一
  • Organizer: 脳心血管抗加齢研究会2016（CCVAA) シンポジウム5「免疫老化から迫る脳心血管疾患の発症機序」
  • Place of Presentation: 秋葉原UDX 4階 NEXT-1, 東京都
  • Year and Date: 2016-12-18
  • Invited
• [Presentation] 慢性炎症と臓器線維化におけるアンジオポエチン様因子2の役割 (2016)
  • Author(s): 尾池雄一
  • Organizer: CVMW2016 心血管代謝週間 合同シンポジウム2「慢性炎症と臓器線維化の分子基盤」
  • Place of Presentation: 東京コンベンションホール 大ホールAB, 東京都
  • Year and Date: 2016-12-16
  • Invited
• [Presentation] Roles of Angiopoietin-like protein 2（ANGPTL2 ）in cardiovascular disease (2016)
  • Author(s): Yuichi OIKE
  • Organizer: 第24回日本血管生物医学会学術集会/第14回日韓血管生物合同シンポジウム Joint Symposium 3 Cardiovascular aging
  • Place of Presentation: 長崎ブリックホール, 長崎市
  • Year and Date: 2016-12-09
  • Int'l Joint Research / Invited
• [Book] 別冊BIO Clinica 慢性炎症と疾患7(1) 心臓と血管の慢性炎症（生活習慣病）10 (2018)
  • Author(s): 門松 毅、尾池雄一
  • Total Pages: 5
  • Publisher: 北隆館・ニューサイエンス社
• [Remarks] 熊本大学大学院生命科学研究部 分子遺伝学分野
  • URL: http://www.kumamoto-u-molgene.jp