Identification of novel miRNAs contributing the onset of atherosclerosis

• Project/Area Number: 17K15991
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Higashijima Yoshiki 東京医科歯科大学, 難治疾患研究所, 日本学術振興会特別研究員 (40780713)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 動脈硬化 / miRNA / 接着因子 / エピジェネティクス / VCAM1 / SELE / atherosclerosis / VCAM-1 / 循環器 / ゲノム / 発現制御

Outline of Final Research Achievements

Cardiovascular disease is one of the leading causes of death in developed countries. Atherosclerosis is responsible for cardiovascular disease and it is expected to develop novel diagnostic markers or therapeutic targets for atherosclerosis. In this study, we examined transcriptional changes of human endothelial cells during inflammatory responses by using microarray and next generation sequences. As a result, we identified a novel miRNA, miR-3679-5p that contributes to the onset of atherosclerosis (i.e. induction of cell adhesion molecules). Exosome is a small vesicle that is secreted into body fluid including blood and urine, and its potential uses as diagnostic marker or drug vehicle are also expected. Now, we are analyzing exosomal miR-3679-5p from human patients serum to examine whether exosomal miR-3679-5p could be useful for diagnostic marker as well as therapeutic target.

Academic Significance and Societal Importance of the Research Achievements

心血管疾患は本邦の死因の第二位の心疾患と第四位の脳血管疾患を合わせた総称であり、その数は第一位の悪性新生物に匹敵する。近年問題となっている国民医療費においても心血管疾患を含む循環器疾患が一位であり、医療経済的に重要な分野である。本研究では、心血管病の主な原因である動脈硬化発症に寄与する新規miRNAとしてmiR-3679-5pを同定した。今後、今回の発見などに基づいて、動脈硬化の病態の理解が進み、その診断法・治療法などが向上して行くことが期待される。

Research Products

• [Int'l Joint Research] UCSD(米国)
• [Int'l Joint Research] UCSD(米国)
• [Journal Article] Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells (2020)
  • Author(s): Higashijima Y, Matsui Y, Shimamura T, Nakaki R, Nagai N, Tsutsumi S, Abe Y, Link VM, Osaka M, Yoshida M, Watanabe R, Tanaka T, Taguchi A, Miura M, Ruan X, Li G, Inoue T, Nangaku M, Kimura H, Furukawa T, Aburatani H, Wada Y, Ruan Y, Glass CK, Kanki Y
  • Journal Title: The EMBO Journal Volume: 39 Issue: 7 Pages: 1-1
  • DOI: 10.15252/embj.2019103949
  • NAID: 120006902140
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular mechanistic insights: The emerging role of SOXF transcription factors in tumorigenesis and development (2019)
  • Author(s): Higashijima Yoshiki、Kanki Yasuharu
  • Journal Title: Seminars in Cancer Biology Volume: - Pages: 39-48
  • DOI: 10.1016/j.semcancer.2019.09.008
  • Peer Reviewed
• [Journal Article] Lysine demethylase 7a regulates the anterior-posterior development in mouse by modulating the transcription of Hox gene cluster (2019)
  • Author(s): Higashijima Yoshiki、Nagai Nao、Kitazawa Taro、Kawamura Yumiko、Taguchi Akashi、Nakada Natsuko、Nangaku Masaomi、Furukawa Tetsushi、Aburatani Hiroyuki、Kurihara Hiroki、Wada Youichiro、Kanki Yasuharu
  • Journal Title: bioRxiv Volume: -
  • DOI: 10.1101/707125
  • Open Access
• [Journal Article] Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells (2018)
  • Author(s): Higashijima Y, Matsui Y, Shimamura T, Tsutsumi S, Nakaki R, Abe Y, Link VM, Osaka M, Yoshida M, Watanabe R, Tanaka T, Taguchi A, Miura M, Inoue T, Nangaku M, Kimura H, Furukawa T, Aburatani H, Wada Y, Glass CK, Kanki Y
  • Journal Title: bioRxiv Volume: - Pages: 456491-456491
  • DOI: 10.1101/456491
  • NAID: 120006902140
  • Open Access / Int'l Joint Research
• [Journal Article] Sodium glucose cotransporter 2 inhibition normalizes glucose metabolism and suppresses oxidative stress in the kidneys of diabetic mice (2018)
  • Author(s): Tanaka Shinji、Sugiura Yuki、Saito Hisako、Sugahara Mai、Higashijima Yoshiki、Yamaguchi Junna、Inagi Reiko、Suematsu Makoto、Nangaku Masaomi、Tanaka Tetsuhiro
  • Journal Title: Kidney International Volume: 94 Issue: 5 Pages: 912-925
  • DOI: 10.1016/j.kint.2018.04.025
  • Peer Reviewed
• [Journal Article] Persistent expression of neutrophil gelatinase-associated lipocalin and M2 macrophage markers and chronic fibrosis after acute kidney injury (2018)
  • Author(s): Saito Hisako、Tanaka Tetsuhiro、Tanaka Shinji、Higashijima Yoshiki、Yamaguchi Junna、Sugahara Mai、Ito Marie、Uchida Lisa、Hasegawa Sho、Wakashima Takeshi、Fukui Kenji、Nangaku Masaomi
  • Journal Title: Physiological Reports Volume: 6 Issue: 10 Pages: e13707-e13707
  • DOI: 10.14814/phy2.13707
  • Peer Reviewed / Open Access
• [Journal Article] Applications of the CRISPR-Cas9 system in kidney research (2017)
  • Author(s): Higashijima Yoshiki、Hirano Seiichi、Nangaku Masaomi、Nureki Osamu
  • Journal Title: Kidney International Volume: 92 Issue: 2 Pages: 324-335
  • DOI: 10.1016/j.kint.2017.01.037
  • Peer Reviewed
• [Journal Article] Vascular adhesion protein-1 enhances neutrophil infiltration by generation of hydrogen peroxide in renal ischemia/reperfusion injury. (2017)
  • Author(s): Tanaka S, Tanaka T, Kawakami T, Takano H, Sugahara M, Saito H, Higashijima Y, Yamaguchi J, Inagi R, Nangaku M.
  • Journal Title: Kidney Int Volume: 印刷中 Issue: 1 Pages: 154-164
  • DOI: 10.1016/j.kint.2017.01.014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 炎症性遺伝子転写制御におけるヒストン脱メチル化の機能解析 (2019)
  • Author(s): 東島佳毅
  • Organizer: 第27回血管生物医学会学術集会
• [Presentation] ヒストン脱メチル化酵素Kdm7aはマウスにおいて前後軸形成を制御する (2019)
  • Author(s): 東島佳毅、永井直、北沢太郎、河村悠美子、南学正臣、栗原裕基、和田洋一郎、古川哲史、神吉康晴
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] ヒストン脱メチル化酵素Kdm7aはHox遺伝子群の転写制御を介して前後軸形成を制御する (2019)
  • Author(s): 東島佳毅、永井直、北沢太郎、河村悠美子、南学正臣、栗原裕基、和田洋一郎、古川哲史、神吉康晴
  • Organizer: 第92回日本生化学会大会
• [Presentation] クロマチン相互解析による血管炎症関連遺伝子の転写制御機構の解明 (2019)
  • Author(s): 東島佳毅
  • Organizer: 第1回ダウン症基礎研究会
• [Presentation] Lysine demethylase 7a regulates anterior-posterior development via modulating Hox gene cluster transcription in mice (2019)
  • Author(s): Higashijima Y, Nagai N, Kitazawa T, Kawamura Y, Nagnaku M, Kurihara H, Wada Y, Kanki Y
  • Organizer: Cell Symposia: Transcriptional Regulation in Evolution, Development, and Disease
  • Int'l Joint Research
• [Presentation] Lysine demthylase 7A and 6A dynamically modulate chromatin looping to control inflammatory gene transcription in human endothelial cells. (2018)
  • Author(s): Higashijima Y, Tsutsumi S, Link VM, Abe Y, Nangaku M, Wada Y, Glass CK, Furukawa T, Kanki Y.
  • Organizer: EMBL Conference: Transcription and Chromatin.
  • Int'l Joint Research
• [Presentation] miRNA-ヒストン修飾による動脈硬化関連遺伝子の転写制御機構解析 (2018)
  • Author(s): 東島佳毅、松井佑介、島村徹平、大坂瑞子、吉田雅幸、南学正臣、和田洋一郎、古川哲史、神吉康晴
  • Organizer: 第41回日本分子生物学会
  • Invited
• [Presentation] Transcriptional control of atherosclerosis-related genes through repressive histone marks and chromosomal interactions (2018)
  • Author(s): 東島佳毅、堤修一、松井佑介、島村徹平、井上剛、南学正臣、和田洋一郎、古川哲史、神吉康晴
  • Organizer: 第91回日本生化学会大会
• [Presentation] MicroRNA-3679-5p modulates the induction of adhesion molecules by targeting histone demethylases, KDM7A and UTX. (2017)
  • Author(s): Yoshiki HIGASHIJIMA, Tsuyoshi INOUE, Masaomi NANGAKU, Tatsuhiko KODAMA, Yasuharu KANKI, Youichiro WADA
  • Organizer: 第43回内藤コンファレンス
• [Presentation] 血管内皮細胞における炎症刺激に応じたmiRNA-ヒストン修飾ネットワーク機構 (2017)
  • Author(s): 東島 佳毅、神吉 康晴、井上 剛、南学 正臣、古川 哲史、和田 洋一郎
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] Lysine Demethylase 6A And 7A Regulated By MicroRNA-3679-5p Mediates TNF-α-induced Inflammatory Signaling In Vascular Endothelium. (2017)
  • Author(s): Yoshiki HIGASHIJIMA,Tsuyoshi INOUE, Masaomi NANGAKU, Youichiro WADA, Tetsushi FURUKAWA,Yasuharu KANKI
  • Organizer: American Heart Association 2017
  • Int'l Joint Research