The role of Endothelial miRNA in the regulation of vascular integrity

• Project/Area Number: 26293130
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Kagoshima University
• Principal Investigator: Yamakuchi Munekazu 鹿児島大学, 医歯学域医学系, 准教授 (20325814)
• Co-Investigator(Kenkyū-buntansha): 丸山 征郎 鹿児島大学, 医歯学総合研究科, 特任教授 (20082282) ; 大山 陽子 鹿児島大学, 医学部・歯学部附属病院, 特任助教 (20583470) ; 竹之内 和則 鹿児島大学, 医学部・歯学部附属病院, 医員 (30646758) ; 清水 利昭 鹿児島大学, 医歯学域医学系, 助教 (50468055) ; 橋口 照人 鹿児島大学, 医歯学域医学系, 教授 (70250917)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000); Fiscal Year 2016: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2014: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
• Keywords: microRNA / 血管内皮細胞 / 糖尿病 / miRNA / 一酸化窒素 / エクソゾーム / 単球 / マイクロRNA / TP53

Outline of Final Research Achievements

Vascular dysfunction is the cause of various diseases, such as diabetes, atherosclerosis, and malignancy. Endothelial cells play a central role in controlling vascular function and maintaining vascular integrity. We identified a set of microRNAs (miRNAs) expressed in vascular endothelial cells, which regulate vascular malfunction. miRNAs are short-chain single-stranded RNA that suppress protein synthesis post-transcriptionally. We focused on several miRNAs expressed in endothelial cells. Among them, miR-424/503 are unique miRNAs, which are upregulated under hypoxic condition. We have shown three major things below. (1) miR-424/503 suppresses the production of vasorelaxant gas, nitric oxide. (2) miR-424/503 changes the phenotype of endothelial cells. (3) Secreted miRNAs alter the function of mononuclear cells.

Research Products

• [Journal Article] PERMEABILITY AND ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR EFFECTS OF BEVACIZUMAB, RANIBIZUMAB, AND AFLIBERCEPT IN POLARIZED RETINAL PIGMENT EPITHELIAL LAYER IN VITRO. (2017)
  • Author(s): Yoshihara N, Terasaki H, Shirasawa M, Kawano H, Sonoda S, Yamakuchi M, Hashiguchi T, Hisatomi T, Ishibashi T, Sakamoto T.
  • Journal Title: Retina Volume: 37(1) Issue: 1 Pages: 179-190
  • DOI: 10.1097/iae.0000000000001117
  • Peer Reviewed
• [Journal Article] Low grade inflammation inhibits VEGF induced HUVECs migration in p53 dependent manner. (2017)
  • Author(s): Panta S, Yamakuchi M, Shimizu T, Takenouchi K, Oyama Y, Koriyama T, Kojo T, Hashiguchi T.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 483 Issue: 2 Pages: 803-809
  • DOI: 10.1016/j.bbrc.2016.12.096
  • Peer Reviewed / Open Access
• [Journal Article] A Switch in the Dynamics of Intra-Platelet VEGF-A from Cancer to the Later Phase of Liver Regeneration after Partial Hepatectomy in Humans (2016)
  • Author(s): Aryal B, Shimizu T, Kadono J, Furoi A, Komokata T, Inoue M, Ikeda S, Fukukura Y, Nakamura M, Yamakuchi M, Hashiguchi T, Imoto Y
  • Journal Title: PLoS One Volume: 11(3) Issue: 3 Pages: e0150446-e0150446
  • DOI: 10.1371/journal.pone.0150446
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SNAP23 Regulates Endothelial Exocytosis of von Willebrand Factor (2015)
  • Author(s): Zhu Q, Yamakuchi M, Lowenstein CJ
  • Journal Title: PLoS One Volume: 10(8) Issue: 8 Pages: e0118737-e0118737
  • DOI: 10.1371/journal.pone.0118737
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Upregulation of non-β Cell-derived Vascular Endothelial Growth FactorA Increases Small Clusters of Insulin producing Cells in the Pancreas. (2014)
  • Author(s): Takenouchi K, Shrestha B, Yamakuchi M, Yoshinaga M, Arimura N, Kawaguchi H, Nagasato T, Feil R, Kawahara K-I, Sakamoto T, Maruyama I, Hashiguchi T.
  • Journal Title: Experimental and Clinical Endocrinology & Diabetes Volume: in press Issue: 05 Pages: 308-15
  • DOI: 10.1055/s-0034-1371811
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2. (2014)
  • Author(s): Huang J, Huffman JE, Yamakuchi M,... Lowenstein CJ, Strachan DP, O'Donnell CJ; CHARGE Consortium Hemostatic Factor Working Group.
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 34(5) Issue: 5 Pages: 1093-1101
  • DOI: 10.1161/atvbaha.113.302088
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Syntaxin-binding protein STXBP5 inhibits endothelial exocytosis and promotes platelet secretion. (2014)
  • Author(s): Zhu Q, Yamakuchi M, Ture S, de la Luz Garcia-Hernandez M, Ko KA, Modjeski KL, LoMonaco MB, Johnson AD, O'Donnell CJ, Takai Y, Morrell CN, Lowenstein CJ.
  • Journal Title: J Clin Invest. Volume: 124 Issue: 10 Pages: 4503-4516
  • DOI: 10.1172/jci71245
  • Peer Reviewed / Open Access
• [Presentation] Co-operation of TNFalpha and VEGF to regulate PAI-1 through synergistically upregulated p53 (2016)
  • Author(s): Sushil Panta, Munekazu Yamakuchi, Toshiaki Shimizu, Kazunori Takenouchi, Yoko Oyama, Teruto Hashiguchi
  • Organizer: The 1st Joint Meeting of ISFP and PA Workshop
  • Place of Presentation: Nippondaira Hotel（静岡県静岡市）
  • Year and Date: 2016-10-17
  • Int'l Joint Research
• [Presentation] miR-22の血管内皮細胞での役割の検討 (2016)
  • Author(s): 竹中 大喜, 山口 宗一, 竹之内 和則, 大山 陽子, 清水 利昭, 郡山 豊泰, 古城 剛, 橋口 照人
  • Organizer: 第63回日本臨床検査医学会学術集会
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市）
  • Year and Date: 2016-09-01
• [Presentation] CalDAG-GEFI分子異常により血小板機能異常を呈した一症例 (2016)
  • Author(s): 古城 剛, 山口 宗一, 吉村 明子, 竹之内 和則, 伊藤 隆, 清水 利昭, 大山 陽子, 郡山 豊泰, Panta Sushil, 松下 昌風, 丸山 征郎, 高嶋 博, 橋口 照人
  • Organizer: 第63回日本臨床検査医学会学術集会
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市）
  • Year and Date: 2016-09-01
• [Presentation] 血液培養陽性データよりみる検出菌とその臨床背景 (2016)
  • Author(s): 大山 陽子, 竹之内 和則, 古城 剛, 郡山 豊泰, 福山 竜子, 山口 宗一, 橋口 照人
  • Organizer: 第63回日本臨床検査医学会学術集会
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市）
  • Year and Date: 2016-09-01
• [Presentation] miRNAによる自然免疫制御機構の解明 (2016)
  • Author(s): 山口 宗一, 郡山 豊泰, 向原 公介, 重久 喜哉, 古城 剛, 清水 利昭, 竹之内 和則, 大山 陽子, 井本 浩, 橋口 照人
  • Organizer: 第63回日本臨床検査医学会学術集会
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市）
  • Year and Date: 2016-09-01
  • Invited
• [Presentation] CalDAG-GEFI分子異常により血小板機能異常を呈した一症例 (2016)
  • Author(s): 古城 剛, 山口 宗一, 吉村 明子, 竹之内 和則, 伊藤 隆史, 清水 利昭, 大山 陽子, 郡山 豊泰, Sushil Panta, 松下 昌風, 丸山 征郎, 高嶋 博, 橋口 照人
  • Organizer: 第38回日本血栓止血学会学術集会
  • Place of Presentation: 奈良春日野国際フォーラム（奈良県奈良市）
  • Year and Date: 2016-06-16
• [Presentation] L.pneumophila感染マクロファージ系細胞におけるmiRNAの役割 (2016)
  • Author(s): 山口 宗一, 郡山 豊泰, 古城 剛, 竹之内 和則, 清水 利昭, 大山 陽子, 松下 昌風, 橋口 照人
  • Organizer: 第38回日本血栓止血学会学術集会
  • Place of Presentation: 奈良春日野国際フォーラム（奈良県奈良市）
  • Year and Date: 2016-06-16
• [Presentation] L.pneumophila感染単核系細胞におけるmiRNA解析 (2015)
  • Author(s): 郡山豊泰、山口宗一、竹之内和則、大山陽子、清水利昭、橋口照人
  • Organizer: 第62回日本臨床検査医学会
  • Place of Presentation: 岐阜県岐阜市 長良川国際会議場
  • Year and Date: 2015-11-19
• [Presentation] Regulation of Tumor Development by microRNAs- Do microRNAs link to cancer-associated thrombosis? (2015)
  • Author(s): Munekazu Yamakuchi，Toshiaki Shimizu，Kazunori Takenouchi，Yoko Oyama，and Teruto Hashiguchi
  • Organizer: 第37回日本血栓止血学会学術集会 学術推進委員会（SPC）シンポジウム1
  • Place of Presentation: 山梨県甲府市 甲府市総合市民会館
  • Year and Date: 2015-05-21
  • Invited
• [Presentation] The significance of miRNA measurement in Legionella pneumophila infection (2015)
  • Author(s): Toyoyasu Koriyama, Munekazu Yamakuchi, Tuyoshi Kojo, Ryuko Fukuyama, Masakaze Matsushita, Teruto Hashiguchi
  • Organizer: 第64回日本医学検査学会
  • Place of Presentation: 福岡県福岡市 福岡国際会議場
  • Year and Date: 2015-05-16
• [Presentation] 直腸がんの血管新生を制御するマイクロRNAの検討 (2014)
  • Author(s): 山口宗一, 清水利昭, 竹之内和則, 大山陽子, 郡山豊秦, 伊藤隆史, 橋口照人
  • Organizer: 第61回日本臨床検査医学会学術集会
  • Place of Presentation: 福岡(福岡国際会議場）
  • Year and Date: 2014-11-22 – 2014-11-25
• [Presentation] non-β細胞由来VEGF-Aはisletを構成しないインスリン産生細胞のsmall clustersを増加させる (2014)
  • Author(s): 竹之内和則、ビニタ・スレスタ、山口宗一、橋口照人
  • Organizer: 第54回 日本臨床化学会 年次学術集会
  • Place of Presentation: 東京（東京大学本郷キャンパス）
  • Year and Date: 2014-09-05 – 2014-09-07
• [Presentation] MIR-503 Modulation of NOS3 Signaling via RICTOR (2014)
  • Author(s): Munekazu Yamakuchi, Teruto Hashiguchi, Charles J Lowenstei
  • Organizer: The 60th SSC
  • Place of Presentation: Milwaukee, USA
  • Year and Date: 2014-06-23 – 2014-06-26
• [Presentation] マイクロRNAによる直腸がん血管新生制御機構の解明 (2014)
  • Author(s): 山口宗一、清水利昭、竹之内和則、大山陽子、橋口照人
  • Organizer: 第36回血栓止血学術集会
  • Place of Presentation: 大阪（大阪国際交流センター）
  • Year and Date: 2014-05-29 – 2014-05-31
• [Presentation] Automatic Integration of All Laboratory Data in the Analysis Server Supporting (2014)
  • Author(s): M. Yamakuchi, Y. Oyama, K. Takenouchi, T. Ito, T. Shimizu, M. Matsushita, T. Hashiguchi
  • Organizer: The 9th Cherry Bloosom Symposium
  • Place of Presentation: Yokohama, Japan（横浜赤レンガ倉庫1号館）
  • Year and Date: 2014-04-17 – 2014-04-19
• [Book] 血管病のmicroRNA (2015)
  • Author(s): 山口宗一
  • Total Pages: 50
  • Publisher: メディカルビュー社
• [Book] 血栓止血血管学 (2015)
  • Author(s): 山口宗一
  • Total Pages: 250
  • Publisher: 金芳堂
• [Book] 広がる血管microRNAの役割 (2014)
  • Author(s): 山口宗一、橋口照人
  • Total Pages: 8
  • Publisher: 臨床化学
• [Book] Post-marketing surveillance of thrombomodulin alfa, a novel treatment of disseminated intravascular coagulation ;Safety and efficacy in 1.032 patients with hematologic malignancy. (2014)
  • Author(s): Teruto Hashiguchi and Munekazu yamakuchi
  • Total Pages: 4
  • Publisher: International Review of Thrombosis