The role of endothelial Stat3 in pathogenesis of aortic dissection

• Project/Area Number: 19K09280
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55030:Cardiovascular surgery-related
• Research Institution: Kurume University
• Principal Investigator: Hirakata Saki 久留米大学, 医学部, 講師 (60597425)
• Co-Investigator(Kenkyū-buntansha): 林 真貴子 久留米大学, 医学部, 助教 (70725027)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 大動脈解離 / 血管内皮細胞 / 免疫複合体 / 炎症細胞 / 内皮細胞 / 分子生物学 / 大血管 / 血管 / STAT3 / 血管内皮

Outline of Research at the Start

大動脈解離は中高年に突然発症する致死性疾患である。分子病態が明らかでないことが新たな診断や治療の開発を妨げている。申請者は、STAT3の機能が細胞毎に異なり、組織破壊・修復の双方を制御することを発見した。STAT3は解離による組織破壊が進行する時期に血管内皮で活性化する。血管内皮は炎症細胞の接着や血管外遊走を制御するゲートウェイ機能を有し、その調節にSTAT3が関与することが報告されているが、解離病態における内皮STAT3の機能や意義は不明である。本研究では、STAT3が血管内皮ゲートウェイ機能を調節し、炎症細胞浸潤を制御するとの仮説検証を通じ、解離における組織破壊・修復機構の解明を目指す。

Outline of Final Research Achievements

Aortic dissection (AD) is a fatal disease that occurs suddenly without preceding symptoms, of which disease mechanism is unknown. Aortic tissue from human AD or mouse AD model showed activation of STAT3, a molecule that mediates inflammation. In mouse model, pathological angiogenesis was observed in a STAT3-dependent manner, which was associated with the deposition of plasma-derived factors including fibrin, immunoglobulins and complement C3. In addition, vascular protective factor adiponectin was deposited in normal aortic tissue, which disappeared upon the AD-inducing stimuli before AD development. These findings suggested that disruption of endothelial barrier function precedes AD development that leads to the deposition of immune complex that triggers destructive inflammation to promote AD.

Academic Significance and Societal Importance of the Research Achievements

大動脈解離は原因不明で前兆なく突然発症し、一旦発症すると致命的になり得る重篤な疾患である。発症が予測できないため解離発症前後の病態は不明であり、逆に発症前後の病態が不明であるため発症予測の手立てがない。大動脈解離における破壊進行に重要とされる炎症応答がどのように惹起されるかは不明である。本研究では、解離発症前に血管保護機能が低下し血漿由来因子による免疫複合体が大動脈壁に沈着し、破壊性炎症を惹起することが示唆された。解離発症前の初期炎症応答に関与するイベントが明らかになったことで、発症の前段階を捉えることが可能になり病態の解明が進むと期待される。

Research Products

• [Journal Article] Ying and Yang of Stat3 in pathogenesis of aortic dissection (2021)
  • Author(s): Aoki Hiroki、Majima Ryohei、Hashimoto Yohei、Hirakata Saki、Ohno-Urabe Satoko
  • Journal Title: Journal of Cardiology Volume: 77 Issue: 5 Pages: 471-474
  • DOI: 10.1016/j.jjcc.2020.10.010
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic Effect of Rapamycin on Aortic Dissection in Mice (2020)
  • Author(s): Hayashi-Hori Makiko、Aoki Hiroki、Matsukuma Miho、Majima Ryohei、Hashimoto Yohei、Ito Sohei、Hirakata Saki、Nishida Norifumi、Furusho Aya、Ohno-Urabe Satoko、Fukumoto Yoshihiro
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 9 Pages: 3341-3341
  • DOI: 10.3390/ijms21093341
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High Salt Intake Worsens Aortic Dissection in Mice (2020)
  • Author(s): Nishida Norifumi、Aoki Hiroki、Ohno-Urabe Satoko、Nishihara Michihide、Furusho Aya、Hirakata Saki、Hayashi Makiko、Ito Sohei、Yamada Hiroshi、Hirata Yuichiro、Yasukawa Hideo、Imaizumi Tsutomu、Tanaka Hiroyuki、Fukumoto Yoshihiro
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 40 Issue: 1 Pages: 189-205
  • DOI: 10.1161/atvbaha.119.313336
  • Peer Reviewed / Open Access
• [Journal Article] Genetic Deletion of Socs3 in Smooth?Muscle Cells Ameliorates Aortic?Dissection in Mice (2020)
  • Author(s): Hirakata Saki、Aoki Hiroki、Ohno-Urabe Satoko、Nishihara Michihide、Furusho Aya、Nishida Norifumi、Ito Sohei、Hayashi Makiko、Yasukawa Hideo、Imaizumi Tsutomu、Hiromatsu Sinichi、Tanaka Hiroyuki、Fukumoto Yoshihiro
  • Journal Title: JACC: Basic to Translational Science Volume: 5 Issue: 2 Pages: 126-144
  • DOI: 10.1016/j.jacbts.2019.10.010
  • Peer Reviewed / Open Access
• [Journal Article] MRTF-A promotes angiotensin II-induced inflammatory response and aortic dissection in mice (2020)
  • Author(s): Ito Sohei、Hashimoto Yohei、Majima Ryohei、Nakao Eichi、Aoki Hiroki、Nishihara Michihide、Ohno-Urabe Satoko、Furusho Aya、Hirakata Saki、Nishida Norifumi、Hayashi Makiko、Kuwahara Koichiro、Fukumoto Yoshihiro
  • Journal Title: PLOS ONE Volume: 15 Issue: 3 Pages: e0229888-e0229888
  • DOI: 10.1371/journal.pone.0229888
  • Peer Reviewed / Open Access
• [Presentation] The role of cellular senescene in aortic dissection (2021)
  • Author(s): E.Nakao, H. Aoki, R. Majima, Y. Hashimoto, R. Shibata, M. Hayashi, S. Ohno- Urabe, A. Furusho, N. Nishida, S. Hirakata and Y. Fukumoto
  • Organizer: ESC Congress 2021
  • Int'l Joint Research
• [Presentation] The Role of Cellular Senescence in Aortic Dissection (2021)
  • Author(s): E. Nakao, H. Aoki, R. Majima, Y. Hashimoto, R. Shibata, M. Hayashi, S. Ohno- Urabe, A. Furusho, N. Nishida, S. Hirakata and Y. Fukumoto
  • Organizer: AHA Scientific Sessions 2021
  • Int'l Joint Research
• [Presentation] 大動脈解離病態における細胞老化の 関与 (2021)
  • Author(s): 中尾英智、青木浩樹、眞島涼平、橋本洋平、柴田怜、林真貴子、大野-浦部聡子 、古荘文、西田憲文、平方佐季、福本義弘
  • Organizer: 第130回 日本循環器学会九州地方会
• [Presentation] The role of B cells and IgG in aortic dissection. (2020)
  • Author(s): N. Nishida, A. Furusho, H. Aoki, S. Hirakata, S. Ito, M. Hayashi, Y. Hashimoto, R. Majima, Y. Fukumoto
  • Organizer: ESC CONGRESS 2020
  • Int'l Joint Research
• [Presentation] Regulation of Extracellular Matri Metabolism in Aortic Dissection (2020)
  • Author(s): N. Nishida, H. Aoki, S. Ohno, M. Nishihara, A. Furusho, S Hirakarta, S.Ito, M. Hayashi, H. Yasukawa, Y. Fukumoto
  • Organizer: The 84th Annual Scientific Meeting of Japanese Circulation Society 2020
• [Presentation] High Salt and IL-17A Cooperatively Worsens Aortic Dissection in Mice (2020)
  • Author(s): N. Nishida, H. Aoki, S. Ohno, M. Nishihara, A. Furusho, S Hirakarta, S.Ito, M. Hayashi, H. Yasukawa, Y. Fukumoto
  • Organizer: The 84th Annual Scientific Meeting of Japanese Circulation Society 2020
• [Presentation] Involvement of Syk in pathogenesis of aortic dissection. (2019)
  • Author(s): Y Hashimoto, H Aoki, R Majima, M Hayashi, S Ito, S Ohno-Urabe, A Furusho, N Nishida, S Hirakata, Y Fukumoto
  • Organizer: The 83th Annual Scientific Meeting of Japanese Circulation Society 2019
• [Presentation] FAK Promotes Tissue Destruction in Murine Model of Aortic Dissection. (2019)
  • Author(s): R Majima, H Aoki, Y Hashimoto, M Hayashi, S Ito, S Ohno-Urabe, A Furusho, N Nishida, S Hirakata, Y Fukumoto
  • Organizer: The 83th Annual Scientific Meeting of Japanese Circulation Society 2019
• [Presentation] Macrophage Overactivation Promotes Aortic Dissection Associated with Medial Expression of Arf and Impaired Proliferation of Smooth Muscle Cells in Mice. (2019)
  • Author(s): S Ohno-Urabe, M Kase, H Aoki, M Nishihara, A Furusho, S Hirakata, N Nishida, S Ito, M Hayashi, Y Fukumoto
  • Organizer: Vascular Discovery: From Genes to Medicine Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] Syk activation is a defense mechanism in murine model of aortic dissection. (2019)
  • Author(s): Y Hashimoto, H Aoki, R Majima, M Hayashi, S Ohno-Urabe, A Furusho, N Nishida, S Hirakata and Y Fukumoto
  • Organizer: ESC CONGRESS 2019
  • Int'l Joint Research
• [Presentation] Activation of focal adhesion kinase is involved in pathogenesis of aortic dissection in mice. (2019)
  • Author(s): R Majima, H Aoki, Y Hashimoto, M Hayashi, S Ohno-Urabe, A Furusho, N Nishida, S Hirakata and Y Fukumoto
  • Organizer: ESC CONGRESS 2019
  • Int'l Joint Research