Pathology of aortic dissection with focal adhesion signal molecule FAK and breakthrough medicine development

• Project/Area Number: 18K15867
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Kurume University
• Principal Investigator: Majima Ryohei 久留米大学, 医学部, 助教 (60811073)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: Focal adhesion kinase / 大動脈解離 / マクロファージ / 平滑筋 / FAK

Outline of Final Research Achievements

In aortic dissection, inflammation caused by stress on the aortic wall and extracellular matrix destruction are important. We created a mouse model of aortic dissection by continuous infusion of β-aminopropionitrile and angiotensin II. In this study, we focused on focal adhesion kinase (FAK), which is an intracellular signal transduction molecule, and investigated its relationship with the pathological condition of dissociation. Administration of FAK inhibitor significantly reduced the severity of aortic dissection, especially in the aortic arch including the ascending aorta. Moreover, mortality was significantly improved by administration of FAK inhibitor. It was suggested that FAK causes tissue destruction in the aortic wall.

Academic Significance and Societal Importance of the Research Achievements

大動脈解離は大動脈中膜が突然断裂する致死的疾患である。社会的責任が大きくなる50代 以上の男性に多く発症し、突然死を来すことがあるが、外科的治療の他に積極的な内科治療は存在しない。本研究の結果からFAKは大動脈壁に病理学的ストレスを伝達して組織破壊を引き起こし、大動脈解離の病因において中心的な役割を果たすことが示唆された。また、FAK阻害薬が解離の増悪抑制と死亡率減少に有効であることが明らかとなり、解離進行阻止療法の開発につながる新しい知見となった。

Research Products

• [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] FAK Promotes Tissue Destruction in Murine Model of Aortic Dissection (2019)
  • Author(s): Majima R, Aoki H, Hashimoto Y, Hayashi Y, Ito S, Ohno-Urabe S, Furusho A, Nishida N, Hirakata S, Fukumoto Y
  • Organizer: 第83回日本循環器学会学術集会(2019年3月29~31日:神奈川)
• [Presentation] 大動脈解離の病因におけるFAKの関与 (2019)
  • Author(s): 眞島 涼平、青木 浩樹、橋本 洋平、林 真貴子、伊東 壮平、大野 聡子、古荘 文、西田 憲史、平方 佐季、福本 義弘
  • Organizer: 第19回日本NO学会学術集会（2019年6月14～15日）
• [Presentation] The role of Focal Adhesion Kinase in pathogenesis of aortic dissection (2019)
  • Author(s): Majima R, Aoki H, Hashimoto Y, Hayashi M, Ohno-Urabe S, Furusho A, Nishida N, Hirakata S, Fukumoto Y
  • Organizer: ESC Congress Paris 2019 September 3
  • Int'l Joint Research
• [Presentation] FAK Promotes Tissue Destruction in Murine Model of Aortic Dissection (2019)
  • Author(s): Majima R, Aoki H, Hashimoto Y, Hayashi Y, Ito S, Ohno-Urabe S, Furusho A, Nishida N, Hirakata S, Fukumoto Y
  • Organizer: 第83回日本循環器学会学術集会（2019年3月29～31日：神奈川）
• [Presentation] Involvement of focal adhesion kinase in pathogenesis of aortic dissection. (2018)
  • Author(s): Majima R, Aoki H, Hashimoto Y, Hayashi Y, Ito S, Ohno-Urabe S, Furusho A, Nishida N, Hirakata S, Fukumoto Y
  • Organizer: The 2nd JCS Council Forum on Basic CardioVascular Research (2018年9月22～23日：奈良)
• [Presentation] Focal adhesion kinase promotes fatal destruction of aortic wall in aortic dissection in mice. (2018)
  • Author(s): Majima R, Aoki H, Hashimoto Y, Hayashi Y, Ito S, Ohno-Urabe S, Furusho A, Nishida N, Hirakata S, Fukumoto Y
  • Organizer: American Heart Association Scientific Sessions 2018, Chicago, IL, USA, November 10-12, 2018
  • Int'l Joint Research
• [Presentation] The role of Syk in pathogenesis of aortic dissection. (2018)
  • Author(s): Hashimoto Y, Aoki H, Majima R, Hayashi Y, Ito S, Ohno-Urabe S, Furusho A, Nishida N, Hirakata S, Fukumoto Y
  • Organizer: The 2nd JCS Council Forum on Basic CardioVascular Research (2018年9月22～23日：奈良)
• [Presentation] Protective Role of Syk in Pathogenesis of Aortic Dissection in Mice. (2018)
  • Author(s): Hashimoto Y, Aoki H, Majima R, Hayashi Y, Ito S, Ohno-Urabe S, Furusho A, Nishida N, Hirakata S, Fukumoto Y
  • Organizer: American Heart Association Scientific Sessions 2018, Chicago, IL, USA, November 10-12, 2018
  • Int'l Joint Research
• [Presentation] Overactivation of macrophage promotes aortic dissection through the induction of Ink4a/Arf and impairment of smooth muscle proliferation in mouse aorta. (2018)
  • Author(s): Ohno-Urabe S, Aoki H, Nishihara M, Furusho A, Hirakata S, Nishida N, Ito S, Hayashi Y, Ito S, Hashimoto Y, Majima R, Fukumoto Y
  • Organizer: ESC Congress 2018, Munich, Germany, August 25-29, 2018
  • Int'l Joint Research
• [Presentation] MRTF-A mediates aortic smooth muscle cell apoptosis and inflammatory response to develop aortic dissection. (2018)
  • Author(s): Ito S, Aoki H, Nishihara M, Ohno-Urabe S, Furusho A, Hirakata S, Nishida N, Hayashi Y, Ito S, Hashimoto Y, Majima R, Kuwahara K, Fukumoto Y
  • Organizer: ESC Congress 2018, Munich, Germany, August 25-29, 2018
  • Int'l Joint Research