The role of cardiac specific long non-coding RNA in pathological mechanism of cardiac hypertrophy and heart failure.

• Project/Area Number: 26670405
• 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): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ノンコーディングRNA / 分子心臓学 / non-coding RNA / 循環器・高血圧

Outline of Final Research Achievements

The re-upregulation of fetal cardiac genes in heart failure has been reported. Using gene trap approach, among embryonic cardiac specific expressed-clones of long non-coding RNA, cardiac specific long non-coding RNA X (CSLR-X) was identified. The newly established CAG promoter-driven CSLR-X (CAG-CSLR-X) transgenic mice showed no differences of cardiac morphology and cardiac function between CAG-CSLR-X Tg (Tg) and their littermate wild-type mice. To investigate the cardiac function of CAG-CSLR-X, we operated transverse aorta constriction model (TAC) using Tg mice. Ultrasonic echocardiography revealed that Tg mice showed preserved cardiac systolic function, as estimated by fractional shortening analysis, compared with their littermate wild-type mice at 4 weeks after TAC surgery.

Academic Significance and Societal Importance of the Research Achievements

lncRNA自体がまだ発表されて間もないため、その解析は主に培養細胞系を用いて行われおり、遺伝子改変マウスの個体を用いた解析はほとんど行われていない。さらにlncRNAと心機能および心疾患の分子機構に関する報告は現在、数少なく、今回の研究は非常に貴重な成果である。lncRNA CSLR-Xの新たな作用機構の解明だけでなく、種々の遺伝子改変マウスを用いることで心臓における分子機構が明らかとなり、さらには心不全病態形成における分子機構の基盤研究だけでなく、心不全の予防医学に向けた新規治療法開発へと期待される。

Research Products

• [Journal Article] Angiopoietin-like protein 2 increases renal fibrosis by accelerating transforming growth factor-β signaling in chronic kidney disease. (2016)
  • Author(s): Jun Morinaga, Tsuyoshi Kadomatsu, Keishi Miyata, Motoyoshi Endo, Kazutoyo Terada, Zhe Tian, Taichi Sugizaki, Hiroki Tanigawa, Jiabin Zhao, Shunshun Zhu, Michio Sato, Kimi Araki, Ken-ichi Iyama, Kengo Tomita, Masashi Mukoyama, Kimio Tomita, Kenichiro Kitamura, Yuichi Oike
  • Journal Title: Kidney International Volume: 89 Issue: 2 Pages: 327-341
  • DOI: 10.1016/j.kint.2015.12.021
  • Peer Reviewed
• [Journal Article] Excess Lymphangiogenesis Cooperatively Induced by Macrophages and CD4D T Cells Drives the Pathogenesis of Lymphedema (2016)
  • Author(s): Ogata F
  • Journal Title: Journal of Investigative Dermatology Volume: 136 Issue: 3 Pages: 706-714
  • DOI: 10.1016/j.jid.2015.12.001
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Angiopoietin-like protein 2 is a multistep regulator of inflammatory neovascularization in a murine model of age-related macular degeneration. (2016)
  • Author(s): M. Hirasawa, K. Takubo, H. Osada, S. Miyake, E. Toda, M. Endo, K. Umezawa, K. Tsubota, Y. Oike and Y. Ozawa
  • Journal Title: J. Biol. Chem. Volume: 291 Issue: 14 Pages: 7373-7385
  • DOI: 10.1074/jbc.m115.710186
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Persistent activation of cGMP-dependent protein kinase by a nitrated cyclic nucleotide via site specific protein S-guanylation (2016)
  • Author(s): Akashi S, Ahmed KA, Sawa T, Ono K, Tsutsuki H, Burgoyne JR, Ida T, Horio E, Prysyazhna O, Oike Y, Rahaman MM, Eaton P, Fujii S, Akaike T.
  • Journal Title: Biochemistry Volume: 55 Issue: 5 Pages: 751-761
  • DOI: 10.1021/acs.biochem.5b00774
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Angiopoietin-like protein 2 promotes inflammatory conditions in the ligamentum flavum in the pathogenesis of lumbar spinal canal stenosis by activating interleukin-6 expression. (2015)
  • Author(s): Nakamura T, Okada T, Endo M, Nakamura T, Oike Y & Mizuta H.
  • Journal Title: Eur Spine J Volume: 24 Issue: 9 Pages: 2001-2009
  • DOI: 10.1007/s00586-015-3835-z
  • Peer Reviewed / Open Access
• [Journal Article] The exacerbating roles of CCAAT/enhancer-binding protein homologous protein (CHOP) in the development of bleomycin-induced pulmonary fibrosis and the preventive effects of tauroursodeoxycholic acid (TUDCA) against pulmonary fibrosis in mice. (2015)
  • Author(s): Tanaka Y, Ishitsuka Y, Hayasaka M, Yamada Y, Miyata K, Endo M, Kondo Y, Moriuchi H, Irikura M, Tanaka K, Mizushima T, Oike Y, Irie T.
  • Journal Title: Pharmacol Res. Volume: 99 Pages: 52-62
  • DOI: 10.1016/j.phrs.2015.05.004
  • Peer Reviewed / Open Access
• [Journal Article] A Muscle-liver-fat signaling axis is essential for central control of adaptive adipose remodeling (2015)
  • Author(s): Shimizu N, Maruyama T, Yoshikawa N, Matsumiya R, Ma Y, Ito N, Tasaka Y, Kuribara-Souta A, Miyata K, Oike Y, Berger S, Schutz G, Takeda S & Tanaka H
  • Journal Title: Nat Commun Volume: - Issue: 1 Pages: 6693-6693
  • DOI: 10.1038/ncomms7693
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ANGPTL2 increases bone metastasis of breast cancer cells through enhancing CXCR4 signaling. (2015)
  • Author(s): Masuda T, Endo M, Yamamoto Y, Odagiri H, Kadomatsu T, Nakamura T, Tanoue H, Ito H, Yugami M, Miyata K, Morinaga J, Horiguchi H, Motokawa I, Terada K, Morioka MS, Manabe I, Iwase H, Mizuta H, Oike Y.
  • Journal Title: Sci Rep. Volume: 5 Issue: 1 Pages: 9170-9170
  • DOI: 10.1038/srep09170
  • Peer Reviewed / Open Access
• [Journal Article] Cdk5rap1-mediated 2-methylthio modification of mitochondrial tRNAs governs protein translation and contributes to myopathy in mice and humans. (2015)
  • Author(s): Wei FY, Zhou B, Suzuki T, Miyata K, Ujihara Y, Horiguchi H, Takahashi N, Xie P, Michiue H, Fujimura A, Kaitsuka T, Matsui H, Koga Y, Mohri S, Suzuki T, Oike Y, Tomizawa K.
  • Journal Title: Cell Metab Volume: 21 Issue: 3 Pages: 413-6
  • DOI: 10.1016/j.cmet.2015.01.019
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] IRAP deficiency attenuates diet-induced obesity in mice through increased energy expenditure. (2015)
  • Author(s): Niwa M, Numaguchi Y, Ishii M, Kuwahata T, Kondo M, Shibata R, Miyata K, Oike Y, Murohara T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 457(1) Issue: 1 Pages: 12-8
  • DOI: 10.1016/j.bbrc.2014.12.071
  • Peer Reviewed
• [Journal Article] Angiopoietin-like protein 2 renders colorectal cancer cells resistant to chemotherapy by activating spleen tyrosine kinase-phosphoinositide 3-kinase-dependent anti-apoptotic signaling. (2014)
  • Author(s): Horiguchi H, Endo M, Miyamoto Y, Sakamoto Y, Odagiri H, Masuda T, Kadomatsu T, Tanoue H, Motokawa I, Terada K, Morioka MS, Manabe I, Baba H, Oike Y.
  • Journal Title: Cancer Science Volume: 105 Issue: 12 Pages: 1550-1559
  • DOI: 10.1111/cas.12554
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Protection afforded by pre- or post-treatment with 4-phenylbutyrateagainst liver injury induced by acetaminophen overdose in mice (2014)
  • Author(s): Daisuke Shimizua, Yoichi Ishitsuka, Keishi Miyata, Yoshiro Tomishima, Yuki Kondo, Mitsuru Irikura, Takao Iwawaki, Yuichi Oike, Tetsumi Irie
  • Journal Title: Pharmacol. Res. Volume: 87 Pages: 26-41
  • DOI: 10.1016/j.phrs.2014.06.003
  • Peer Reviewed
• [Journal Article] The adipocyte-inducible secreted phospholipases PLA2G5 and PLA2G2E play distinct roles in obesity. (2014)
  • Author(s): Sato H, Taketomi Y, Ushida A, Isogai Y, Kojima T, Hirabayashi T, Miki Y, Yamamoto K, Nishito Y, Kobayashi T, Ikeda K, Taguchi R, Hara S, Ida S, Miyamoto Y, Watanabe M, Baba H, Miyata K, Oike Y, Gelb MH, Murakami M.
  • Journal Title: Cell Metab. Volume: 20 Issue: 1 Pages: 119-132
  • DOI: 10.1016/j.cmet.2014.05.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Diverse roles of ANGPTL2 in physiology and pathophysiology. (2014)
  • Author(s): Kadomatsu T, Endo M, Miyata K, Oike Y.
  • Journal Title: Trends Endocrinol Metab. Volume: 25(5) Issue: 5 Pages: 245-54
  • DOI: 10.1016/j.tem.2014.03.012
  • Peer Reviewed / Open Access
• [Journal Article] Tissue Inhibitor of Metalloproteinase-3 Knockout Mice Exhibit Enhanced Energy Expenditure through Thermogenesis (2014)
  • Author(s): Hanaoka Y, Yasuda O, Soejima H, Miyata K, Yamamoto E, Izumiya Y, Maeda N, Ohishi M, Rakugi H, Oike Y, Kim-Mitsuyama S, Ogawa H
  • Journal Title: PLoS One Volume: 9 Issue: 4 Pages: e94930-e94930
  • DOI: 10.1371/journal.pone.0094930
  • Peer Reviewed / Open Access
• [Journal Article] TMEM65 is a mitochondrial inner-membrane protein. (2014)
  • Author(s): Naotaka Nishimura, Tomomi Gotoh, Yuichi Oike, Masato Yano
  • Journal Title: PeerJ Volume: 2 Pages: e349-e349
  • DOI: 10.7717/peerj.349
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway. (2014)
  • Author(s): Yoshizawa T, Karim Md. F, Sato Y, Senokuchi T, Miyata K, Fukuda T, Go C, Tasaki M, Uchimura K, Kadomatsu T, Tian Z, Smolka C, Sawa T, Kakeya M, Tomizawa K, Ando Y, Araki E, Akaike T, Braun T, Oike Y, Bober E, Yamagata K.
  • Journal Title: Cell Metab. Volume: 9 Issue: 4 Pages: 712-721
  • DOI: 10.1016/j.cmet.2014.03.006
  • Peer Reviewed / Open Access
• [Journal Article] Prolyl-4-hydroxylase domain 3 (PHD3) is a critical terminator for cell survival of macrophages under stress conditions. (2014)
  • Author(s): Swain L, Wottawa M, Oike Y, et al.
  • Journal Title: J. Leukoc. Biol. Volume: 96 Issue: 3 Pages: 365-375
  • DOI: 10.1189/jlb.2hi1013-533r
  • Peer Reviewed
• [Journal Article] Serum ANGPTL2 levels reflect clinical features of breast cancer patients: implications for the pathogenesis of breast cancer metastasis. (2014)
  • Author(s): Endo M, Yamamoto Y, Nakano M, Masuda T, Odagiri H, Horiguchi H, Miyata K, Kadomatsu T, Motokawa I, Okada S, Iwase H, Oike Y.
  • Journal Title: The International Journal of Biological Markers Volume: 印刷中 Issue: 3 Pages: 0-0
  • DOI: 10.5301/jbm.5000080
  • Peer Reviewed / Open Access
• [Journal Article] Role of endothelial cell-derived angptl2 in vascular inflammation leading to endothelial dysfunction and atherosclerosis progression. (2014)
  • Author(s): Horio E, Kadomatsu T, Miyata K, Arai Y, Hosokawa K, Doi Y, et al.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 34 Issue: 4 Pages: 790-800
  • DOI: 10.1161/atvbaha.113.303116
  • Peer Reviewed / Open Access
• [Presentation] 生活習慣病の分子基盤解明と治療戦略～健康寿命延伸に挑む～ (2016)
  • Author(s): 尾池 雄一
  • Organizer: 糖尿病と肥満における最新知見
  • Place of Presentation: 名古屋市
  • Year and Date: 2016-03-24
  • Invited
• [Presentation] Introduction for Cutting Edge in Advanced Genomic Medicine to Elucidate the Molecular Basis of the Cardiovascular System: From Development to Disease (2016)
  • Author(s): 尾池 雄一
  • Organizer: 第80回日本循環器学会学術集会 シンポジウム21 「最新ゲノム医学から探る心血管システムの分子基盤～発生から病態まで～」
  • Place of Presentation: 東北大学百周年記念会館(宮城県仙台市青葉区）
  • Year and Date: 2016-03-20
  • Invited
• [Presentation] 生活習慣病・がんの共通分子機構とSASPとしてのアンジオポエチン様因子2シグナル (2015)
  • Author(s): 門松 毅、尾池 雄一
  • Organizer: BMB 2015(第38回日本分子生物学会年会 第88回日本生化学会大会 合同大会）
  • Place of Presentation: 神戸ポートアイランド（神戸市中央区）
  • Year and Date: 2015-12-03
• [Presentation] がんと心血管疾患の共通分子基盤解明 (2015)
  • Author(s): 尾池 雄一
  • Organizer: 脳心血管抗加齢研究会2015 シンポジウム3「炎症・免疫応答を機軸とした癌・血管病の000新規治療戦略」
  • Place of Presentation: 梅田スカイビル（大阪市北区大淀中）
  • Year and Date: 2015-11-29
  • Invited
• [Presentation] Tumor cell-derived Angiopoietin-like protein 2 is a crucial driver of metastasis (2015)
  • Author(s): Endo M & Oike Y
  • Organizer: 2015 Annual Meeting od Vascular Science & Medicine Organization Session II「Tumor Angiogenesis and Metastasis」
  • Place of Presentation: MBC Samjoo Art Hall（韓国釜山)
  • Year and Date: 2015-10-16
  • Invited
• [Presentation] 生活習慣病とがんの共通分子病態～健康長寿社会実現化を目指して～ (2015)
  • Author(s): 尾池 雄一
  • Organizer: 東北エイジングサミット ―加齢制御研究から臨床まで―
  • Place of Presentation: 仙台国際センター（宮城県仙台市青葉区）
  • Year and Date: 2015-09-27
  • Invited
• [Presentation] 生活習慣病の分子基盤解明と治療戦略～健康長寿社会実現へ向けて～ (2015)
  • Author(s): 尾池 雄一
  • Organizer: 第4回 MetS Forum 徳島 ～メタボリックシンドロームの克服に向けて～
  • Place of Presentation: ホテルクレメント徳島（徳島市寺島本町西）
  • Year and Date: 2015-08-26
  • Invited
• [Presentation] がん組織内血管代謝ニッシェによる分子記憶形成とがん病態進展の分子機構The mechanisms of tumor progression through molecular memory constituted by vasculo-metabolic niche in tumor tissue (2015)
  • Author(s): 尾池 雄一
  • Organizer: ”臓器の記憶” 国際シンポジウム2015
  • Place of Presentation: 東京コンベンションホール（東京都中央区京橋）
  • Year and Date: 2015-08-23
  • Invited
• [Presentation] Role of ANGPTL2 in Obesity/Diabetes and Cardiovascular Diseases (2015)
  • Author(s): 尾池 雄一
  • Organizer: 第9回 Hypertension and Metabolic Syndrome Symposium
  • Place of Presentation: ヒルトン大阪（大阪市北区梅田）
  • Year and Date: 2015-06-27
  • Invited
• [Presentation] 心血管病の分子病態解明～健康長寿社会を目指して～ (2015)
  • Author(s): 尾池 雄一
  • Organizer: 第2回仙台先進循環器研究会
  • Place of Presentation: 東北大学（宮城県仙台市）
  • Year and Date: 2015-06-20
  • Invited
• [Presentation] 生活習慣病とがんの共通分子病態～健康長寿社会を目指して～ (2015)
  • Author(s): 尾池 雄一
  • Organizer: 第78回神奈川県内科医学会集談会共催セミナー
  • Place of Presentation: 横須賀市医師会館 大会議室（横須賀市新港町）
  • Year and Date: 2015-02-14
  • Invited
• [Presentation] アンジオポエチン様因子と生活習慣関連疾患 (2014)
  • Author(s): 尾池 雄一
  • Organizer: 第35回日本肥満学会
  • Place of Presentation: シーガイアコンベンションホール（宮崎県宮崎市山崎町）
  • Year and Date: 2014-10-24 – 2014-10-25
  • Invited
• [Presentation] Role of ANGPTL2 in obesity and insulin resistance (2014)
  • Author(s): 尾池 雄一
  • Organizer: ICDM2014 (International Conference on Diabetes and Metabolism)
  • Place of Presentation: KINTEX Exhibition Center Ⅱ, Gyeonggido, Korea（京畿道高陽市, 韓国）
  • Year and Date: 2014-10-16 – 2014-10-18
  • Invited
• [Presentation] Tumor cell-derived angiopoietin-like protein ANGPTL2 is a critical driver of metastasis (2014)
  • Author(s): 尾池 雄一
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市西区みなとみらい）
  • Year and Date: 2014-09-25 – 2014-09-27
  • Invited
• [Presentation] 生体恒常性とその変容による疾患発症の分子機構解明～健康長寿社会を目指して～ (2014)
  • Author(s): 尾池 雄一
  • Organizer: 第七回香川脳心腎GOCR研究会
  • Place of Presentation: リーガホテルゼスト高松 3階 ｢ダイヤモンド｣（高松市古新町）
  • Year and Date: 2014-08-27
  • Invited
• [Presentation] Diverse roles of ANGPTL2 signaling in physiology and patho-physiology (2014)
  • Author(s): 尾池 雄一
  • Organizer: Taishan Academic Forum on Cancer & Immune Signaling Pathways And First Session Stem Cell Immunology Qilu International Forum
  • Place of Presentation: Dongshan Hotel Building 6, Yantai,China （烟台市，中国）
  • Year and Date: 2014-08-09 – 2014-08-11
  • Invited
• [Presentation] アンジオポエチン様因子2による生体の恒常性維持と疾患 (2014)
  • Author(s): 尾池 雄一
  • Organizer: 第35回日本炎症・再生医学会
  • Place of Presentation: 万国津梁館（沖縄県名護市喜瀬）
  • Year and Date: 2014-07-01 – 2014-07-04
  • Invited
• [Presentation] 心血管病の分子病態 ～慢性炎症の観点から～ (2014)
  • Author(s): 尾池 雄一
  • Organizer: 千葉心血管病研究会 2014
  • Place of Presentation: ホテル ザ・マンハッタン 2階「ルーナ」（千葉市美浜区ひび野）
  • Year and Date: 2014-06-27
  • Invited
• [Presentation] 生体恒常性維持機構とアンチエイジング (2014)
  • Author(s): 尾池 雄一
  • Organizer: 第14回日本抗加齢医学会総会
  • Place of Presentation: 大阪国際会議場(大阪府大阪市北区中之島）
  • Year and Date: 2014-06-06 – 2014-06-08
  • Invited
• [Presentation] アンジオポエチン様因子の観点からインスリン抵抗性の分子基盤を考える (2014)
  • Author(s): 尾池 雄一
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪国際会議場（10F Room 1003）(大阪府大阪市北区中之島）
  • Year and Date: 2014-05-22 – 2014-05-24
  • Invited
• [Presentation] Metabolic alterations in the tumor microenvironment accelerates tumor cell invasivity and metastasis through epigenetic regulation of ANGPTL2 (2014)
  • Author(s): 尾池 雄一
  • Organizer: 第18回国際血管生物学会
  • Place of Presentation: 京都みやこめっせ（京都府京都市左京区岡崎成勝寺町）
  • Year and Date: 2014-04-14 – 2014-04-17
  • Invited
• [Book] Thyroid Cancer Explore 2(1) (2016)
  • Author(s): 遠藤元誉、尾池雄一
  • Total Pages: 6
  • Publisher: メディカルレビュー社
• [Book] 膨大なデータを徹底整理する サイトカイン・増殖因子キーワード事典 (2015)
  • Author(s): 門松 毅、尾池雄一
  • Total Pages: 3
  • Publisher: 洋土社
• [Book] series モデル動物利用マニュアル 疾患モデルの作製と利用 脂質代謝異常と関連疾患 下巻 (2015)
  • Author(s): 宮田敬士、尾池雄一
  • Total Pages: 8
  • Publisher: エル・アイ・シー
• [Book] series モデル動物利用マニュアル 疾患モデルの作製と利用-脂質代謝異常と関連疾患 下巻 (2015)
  • Author(s): 尾池雄一
  • Total Pages: 2
  • Publisher: エル・アイ・シー
• [Book] 血管医学 16(4) (2015)
  • Author(s): 門松毅、尾池雄一
  • Total Pages: 8
  • Publisher: メディカルレビュー社
• [Book] 別冊 BIO Clinica 慢性炎症と疾患「慢性炎症制御による加齢関連疾患治療の展望」 Perspectives of therapeutic strategy for age-related disease by modulating chronic inflammation 4(2) (2015)
  • Author(s): 門松毅、尾池雄一
  • Total Pages: 7
  • Publisher: 北隆館 ニュー・サイエンス社館 ニュー・サイエンス社
• [Book] Inflamm Regen 35 (2015)
  • Author(s): Oike Y, Kadomatsu T & Endo M.
  • Total Pages: 10
  • Publisher: 日本炎症・再生医学会
• [Book] Inflamm Regen 35 (2015)
  • Author(s): Oike Y
  • Total Pages: 10
  • Publisher: 日本炎症・再生医学会
• [Book] 産科と婦人科 Vol.82(2) (2015)
  • Author(s): 遠藤 元誉, 尾池 雄一
  • Total Pages: 106
  • Publisher: 診断と治療社
• [Book] 医学のあゆみ Vol.250(9) (2015)
  • Author(s): 門松 毅, 尾池 雄一
  • Total Pages: 251
  • Publisher: 医歯薬出版株式会社
• [Book] series モデル動物利用マニュアル 疾患モデルの作製と利用－脂質代謝異常と関連疾患 上巻 (2015)
  • Author(s): 尾池 雄一, 佐々木 雄彦, 村上 誠, 矢作 直也
  • Total Pages: 477
  • Publisher: 株式会社エル・アイ・シー
• [Book] Medical Science Digest Vol.40(11) (2014)
  • Author(s): 門松 毅, 尾池 雄一
  • Total Pages: 45
  • Publisher: ニューサイエンス社