Elucidation of the functions of long non-coding RNA regulating cardiac hypertrophy and failure

• Project Area: Neo-taxonomy of noncoding RNAs
• Project/Area Number: 17H05599
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: 尾野 亘 京都大学, 医学研究科, 准教授 (00359275)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000); Fiscal Year 2018: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
• Keywords: 心肥大 / 心不全 / 非コードRNA / long non-coding RNA

Outline of Annual Research Achievements

非コードRNAの多くを占める長鎖非コードRNA (lncRNA)に関しては、心不全において多くのlncRNA発現が変化することは知られているものの、個々の機能は未知である。我々は、心肥大、心不全をきたしたマウス心臓で有意に上昇する長鎖非コードRNAを網羅的に解析し、その機能を検討することとした。まず、マウス大動脈縮窄モデルを作成し、心肥大、心不全心で高発現していたlong intergenic non-coding RNA（lincRNA）を同定し、lincRNA-Hypertrophy1-10と名づけた。中でも、lincRNA-hypertrophy5は、心筋と骨格筋に特異的に発現するlincRNAである。 まず、RACE法にてこの全長を明らかにした。次にこの欠損マウスを作製したところ、野生型マウスに比較して心臓が小さく、また心臓に圧負荷をかけると代償できずに心不全を呈した。ビオチン化lincRNA-hypertrophy5と肥大心より抽出した核タンパクを結合させ、回収したタンパク質を質量分析で解析したところ、最も特異的に結合するタンパク質は、PURalphaというDNA/RNA結合タンパク質であった。lincRNA-hypertrophy5欠損マウスにおいては、PURalphaが過剰に働くことがミオシン重鎖蛋白の減少と線維芽細胞の減少、さらに心筋細胞の縮小につながることが明らかとなった。さらにヒト心筋生検組織におけるlincRNA-hypertrophy5発現を確認したところ、心機能の悪化とともに発現が減少しており、lincRNA-hypertrophy5発現が心機能を保持している可能性が示唆された。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] MiR-33a is a therapeutic target in SPG4-related hereditary spastic paraplegia human neurons (2019)
  • Author(s): Nakazeki F、Tsuge I、Horie T、Imamura K、Tsukita K、Hotta A、Baba O、Kuwabara Y、Nishino T、Nakao T、Nishiga M、Nishi H、Nakashima Y、Ide Y、Koyama S、Kimura M、Tsuji S、Naitoh M、Suzuki S、Izumi Y、Kawarai T、Kaji R、Kimura T、Inoue H、Ono K
  • Journal Title: Clinical Science Volume: 133 Issue: 4 Pages: 583-595
  • DOI: 10.1042/cs20180980
  • NAID: 120006937614
  • Peer Reviewed / Open Access
• [Journal Article] Hepatokine α1-Microglobulin Signaling Exacerbates Inflammation and Disturbs Fibrotic Repair in Mouse Myocardial Infarction (2018)
  • Author(s): Hakuno Daihiko、Kimura Masahiro、Ito Shinji、Satoh Junko、Nakashima Yasuhiro、Horie Takahiro、Kuwabara Yasuhide、Nishiga Masataka、Ide Yuya、Baba Osamu、Nishi Hitoo、Nakao Tetsushi、Nishino Tomohiro、Nakazeki Fumiko、Koyama Satoshi、Hanada Ritsuko、Randolph Ruiz R.、Endo Jin、Kimura Takeshi、Ono Koh
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1-17
  • DOI: 10.1038/s41598-018-35194-w
  • NAID: 120006645320
  • Peer Reviewed / Open Access
• [Journal Article] SREBF1/MicroRNA-33b Axis Exhibits Potent Effect on Unstable Atherosclerotic Plaque Formation In Vivo (2018)
  • Author(s): Nishino T、Horie T、Baba O、Sowa N、Hanada R、Kuwabara Y、Nakao T、Nishiga M、Nishi H、Nakashima Y、Nakazeki F、Ide Y、Koyama S、Kimura M、Nagata M、Yoshida K、Takagi Y、Nakamura T、Hasegawa K、Miyamoto S、Kimura T、Ono K.
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 38 Issue: 10 Pages: 2460-2473
  • DOI: 10.1161/atvbaha.118.311409
  • Peer Reviewed / Open Access
• [Journal Article] Circulating markers of collagen types I, III, and IV in patients with dilated cardiomyopathy: relationships with myocardial collagen expression (2018)
  • Author(s): Nagao Kazuya、Inada Tsukasa、Tamura Akinori、Kajitani Kenji、Shimamura Kiyotaka、Yukawa Hiroshi、Aida Kenji、Sowa Naoya、Nishiga Masataka、Horie Takahiro、Makita Toshinori、Ono Koh、Tanaka Masaru
  • Journal Title: ESC Heart Failure Volume: 5 Issue: 6 Pages: 1044-1051
  • DOI: 10.1002/ehf2.12360
  • Peer Reviewed / Open Access
• [Journal Article] Loss of periostin ameliorates adipose tissue inflammation and fibrosis in vivo (2018)
  • Author(s): Nakazeki Fumiko、Nishiga Masataka、Horie Takahiro、Nishi Hitoo、Nakashima Yasuhiro、Baba Osamu、Kuwabara Yasuhide、Nishino Tomohiro、Nakao Tetsushi、Ide Yuya、Koyama Satoshi、Kimura Masahiro、Tsuji Shuhei、Sowa Naoya、Yoshida Shigeo、Conway Simon J.、Yanagita Motoko、Kimura Takeshi、Ono Koh
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 8553-8553
  • DOI: 10.1038/s41598-018-27009-9
  • NAID: 120006510274
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MicroRNA-33 regulates the population of peripheral inflammatory Ly6Chigh monocytes through dual pathways. (2018)
  • Author(s): Baba O, Horie T, Hakuno D, Nakashima Y, Nishi H, Kuwabara Y, Nakao T, Nishiga M, Nishino T, Ide Y, Nakazeki F, Koyama S, Kimura M, Hanada R, Kawahara M, Kimura T, and Ono K.
  • Journal Title: Mol Cell Biol. Volume: 38 Issue: 14 Pages: 1-17
  • DOI: 10.1128/mcb.00604-17
  • Peer Reviewed / Open Access
• [Journal Article] Long Non-Coding RNAs as Key Regulators of Cardiovascular Diseases (2018)
  • Author(s): Ono K, Kuwabara Y, Horie T, Kimura T.
  • Journal Title: Circulation Journal Volume: 82 Issue: 5 Pages: 1231-1236
  • DOI: 10.1253/circj.CJ-18-0169
  • NAID: 130006725985
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-33 regulates the population of peripheral inflammatory Ly6Chigh monocytes through dual pathways. (2018)
  • Author(s): Baba O, Horie T, Nakao T, Hakuno D, Nakashima Y, Nishi H, Kuwabara Y, Nishiga M, Nishino T, Ide Y, Nakazeki F, Koyama S, Kimura M, Hanada R, Kawahara M, Kimura T, and *Ono K.
  • Journal Title: Mol Cell Biol. Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Long Non-Coding RNAs as Key Regulators of Cardiovascular Diseases (2018)
  • Author(s): Ono K, Kuwabara Y, Horie T, Kimura T.
  • Journal Title: Circulation J. Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Genetic Ablation of MicroRNA-33 Attenuates Inflammation and Abdominal Aortic Aneurysm Formation via Several Anti-Inflammatory Pathways. (2017)
  • Author(s): Nakao T, Horie T, Baba O, Nishiga M, Nishino T, Izuhara M, Kuwabara Y, Nishi H, Usami S, Nakazeki F, Ide Y, Koyama S, Kimura M, Sowa N, Ohno S, Aoki H, Hasegawa K, Sakamoto K, Minatoya K, Kimura T, Ono K.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 37 Issue: 11 Pages: 2161-2170
  • DOI: 10.1161/atvbaha.117.309768
  • Peer Reviewed / Open Access
• [Journal Article] Imbalanced expression of polycistronic miRNA in acute myeloid leukemia. (2017)
  • Author(s): Kotaki R, Higuchi H, Ogiya D, Katahira Y, Kurosaki N, Yukihira N, Ogata J, Yamamoto H, Mohamad Alba S, Azhim A, Kitajima T, Inoue S, Morishita K, Ono K, Koyama-Nasu R, Kotani A.
  • Journal Title: Int J Hematol. Volume: 106 Issue: 6 Pages: 811-819
  • DOI: 10.1007/s12185-017-2314-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dynamic changes of serum microRNA-122-5p through therapeutic courses indicates amelioration of acute liver injury accompanied by acute cardiac decompensation. (2017)
  • Author(s): Satoshi Koyama, Takashi Kuragaichi, Yukihito Sato, Yasuhide Kuwabara, Shunsuke Usami, Takahiro Horie, Osamu Baba, Daihiko Hakuno, Yasuhiro Nakashima, Tomohiro Nishino, Masataka Nishiga, Tetsushi Nakao, Hidenori Arai, Takeshi Kimura, Koh Ono
  • Journal Title: ESC Heart Failure Volume: 4 Issue: 2 Pages: 112-121
  • DOI: 10.1002/ehf2.12123
  • Peer Reviewed / Open Access
• [Journal Article] Prevention of neointimal formation using miRNA-126-containing nanoparticle-conjugated stents in a rabbit model. (2017)
  • Author(s): Izuhara M, Kuwabara Y, Saito N, Yamamoto E, Hakuno D, Nakashima Y, Horie T, Baba O, Nishiga M, Nakao T, Nishino T, Nakazeki F, Ide Y, Kimura M, Kimura T, Ono K.
  • Journal Title: PLoS One Volume: 12(3) Issue: 3 Pages: e0172798-e0172798
  • DOI: 10.1371/journal.pone.0172798
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol. (2016)
  • Author(s): Nishiga M, Horie T, Kuwabara Y, Nagao K, Baba O, Nakao T, Nishino T, Hakuno D, Nakashima Y, Nishi H, Nakazeki F, Ide Y, Koyama S, Kimura M, Hanada R, Nakamura T, Inada T, Hasegawa K, Conway SJ, Kita T, Kimura T, Ono K.
  • Journal Title: Circ Res. Volume: - Issue: 5 Pages: 835-847
  • DOI: 10.1161/circresaha.116.309528
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] SREBF1/MicroRNA-33b axis exhibits potent effect on unstable atherosclerotic plaque formation in vivo (2018)
  • Author(s): Koh Ono
  • Organizer: XVIIIth International Symposium on Atherosclerosis.
  • Int'l Joint Research / Invited
• [Presentation] Functions of microRNA-33a/b on inflammation and atherosclerosis (2018)
  • Author(s): Koh Ono
  • Organizer: China-Japan International Conference on Atherosclerosis 2018
  • Int'l Joint Research / Invited
• [Presentation] A Novel Long Intergenic Noncoding RNA, LincRNA-Hy5, Underlies the Heart Development and Guards the Heart from Pressure Overload (2018)
  • Author(s): 尾野 亘
  • Organizer: 第1回日本循環器学会基礎研究フォーラム
  • Invited
• [Presentation] SREBF1/MicroRNA-33b axis は不安定プラークの形成に重要である (2018)
  • Author(s): 尾野 亘
  • Organizer: 第50回日本動脈硬化学会総会・学術集会
  • Invited
• [Presentation] マイクロRNAと心血管疾患、代謝性疾患 (2018)
  • Author(s): 尾野 亘
  • Organizer: 第66回日本心臓病学会
  • Invited
• [Presentation] MicroRNA-33の欠損は複数の抗炎症経路を介して大動脈瘤の形成を抑制する (2018)
  • Author(s): 尾野 亘
  • Organizer: 第59回日本脈管学会総会
  • Invited
• [Presentation] Novel Long Intergenic Noncoding RNA, Lionheart, Guards the Heart from Pressure Overload (2018)
  • Author(s): Kuwabara Y, Horie T, Baba O, Nishiga M, Nakao M, Nishino T, Nakazeki F, Koyama S, Kimura T, Ono K.
  • Organizer: 第82回日本循環器学会
• [Presentation] MicroRNA-33b promotes atherosclerotic plaque formation in Apoe-/- mice (2018)
  • Author(s): Nishino T, Horie T, Baba O, Kuwabara Y, Hakuno D, Nakashima Y, Nakao T, Nishiga M, Kimura T, Ono K.
  • Organizer: 第82回日本循環器学会
• [Presentation] Roles of microRNAs in cardiovascular diseases (2017)
  • Author(s): Koh Ono
  • Organizer: 2nd International Symposium for Noncoding RNA Neo-taxonomy In conjunction with Tokyo RNA Club 23rd meeting
  • Int'l Joint Research / Invited
• [Presentation] MicroRNA-33b promotes atherosclerotic plaque formation in Apoe-/- mice. (2017)
  • Author(s): Ono K, Nishino T, Horie T, Kuwabara Y, Nakao T, Nishiga M, Ide Y, Nakazeki F, Koyama S, Kimura M, Kimura T.
  • Organizer: 43rd Naito Conference Noncoding RNA：Biology, Chemistry, & Diseases
  • Int'l Joint Research
• [Presentation] MicroRNA-33b promotes atherosclerotic plaque formation in Apoe-/- mice. (2017)
  • Author(s): Nishino T, Horie T, Kuwabara Y, Nakao T, Nishiga M, Ide Y, Nakazeki F, Koyama S, Kimura M, Kimura T, Ono K
  • Organizer: American Heart Association Scientific Sessions 2017
  • Int'l Joint Research
• [Remarks] 京都大学循環器内科 分子循環器グループ
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/metabolic/
• [Remarks] 心血管疾患分子機構解明グループ
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/metabolic/
• [Patent(Industrial Property Rights)] 遺伝性痙性対麻痺(Hereditary Spastic Paraplegia; HSP)SPG4 に対するmicroRNA-33a抑制療法 (2018)
  • Inventor(s): 尾野 亘、井上治久、今村恵子、堀江貴裕、中関典子
  • Industrial Property Rights Holder: 尾野 亘、井上治久、今村恵子、堀江貴裕、中関典子
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-119251
  • Filing Date: 2018
• [Patent(Industrial Property Rights)] miR-33bノックインマウスによる非アルコール性脂肪肝炎モデル (2018)
  • Inventor(s): 尾野 亘、堀江貴裕、西野共達
  • Industrial Property Rights Holder: 尾野 亘、堀江貴裕、西野共達
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
  • Overseas