The role of Syk in pathogenesis of arctic dissection

• Project/Area Number: 17K10770
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular surgery
• Research Institution: Kurume University
• Principal Investigator: FURUSHO AYA 久留米大学, 医学部, 助教 (80597427)
• Co-Investigator(Kenkyū-buntansha): 青木 浩樹 久留米大学, 付置研究所, 教授 (60322244) ; 田中 啓之 久留米大学, 医学部, 教授 (70197466)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 大動脈解離 / 免疫グロブリン / Syk / B細胞

Outline of Final Research Achievements

We examined the role of Syk in pathogenesis of arctic dissection (AD) using human AD tissue and mouse model of AD. Immunohistochemical staining of human AD tissue revealed that B cells were enriched at the entry site of AD. B cell infiltration and Syk activation were observed in mouse model of AD. Unexpectedly, administration of Syk inhibitor worsened AD, indicating the protective role of Syk. In B cell-deficient muMT mouse, BAPN+AngII induced significantly less severe AD compared to wild type. Depositions of IgG and fibrinogen, one of the endogenous antigen for natural IgG, were observed after BAPN+AngII infusion before and after AD development in wild type mice. Deposition of fiblinogen was also observed in muMT mice after BAPN+AngII infusion. Infusion of IgG to muMT worsened AD. Therefore, Syk is protective against AD, while B cells and IgG promote AD. Our findings may provide the conceptual foundation of the diagnostic and therapeutic strategies for AD.

Academic Significance and Societal Importance of the Research Achievements

本研究では、大動脈解離におけるB細胞および免疫制御分子Sykの役割を解明することを目的とした。解離病態ではSykが組織保護的に作用し、IgGが組織破壊を統合的に制御する可能性を見出した。IgGの作用は多面性があるが、主に炎症促進と炎症抑制に大別される。今後、IgGの作用を個別に検討することで、解離病態における組織破壊と組織保護のインバランスを制御するメカニズムが明らかになると期待される。近年、IgGの抑制型Fcγ受容体の作用を増強し免疫抑制シグナルを導入する創薬が開発されつつあり、本研究の成果から解離病態の組織破壊に対する抑制療法の開発が可能になると考えられる。

Research Products

• [Journal Article] High Salt Intake Worsens Aortic Dissection in Mice: Involvement of IL17A-Dependent Extracellular Matrix Metabolism. (2020)
  • Author(s): Nishida N, Aoki H, Ohno-Urabe S, Nishihara M, Furusho A, Hirakata S, Hayashi M, Ito S, Yamada H, Hirata Y, Yasukawa H, Imaizumi T, Tanaka H, Fukumoto Y
  • Journal Title: Arterioscler Thromb Vasc Biol (in press) Volume: -
• [Journal Article] Genetic Deletion of Socs3 in Smooth Muscle Cells Ameliorates Aortic Dissection in Mice. (2020)
  • Author(s): Hirakata S, Aoki H, Ohno-Urabe S, Nishihara M, Furusho A, Nishida N, Ito S, Hayashi M, Yasukawa H, Imaizumi T, Hiromatsu S, Tanaka H, Fukumoto Y
  • Journal Title: JACC Basic Transl Sci (in press) Volume: -
• [Journal Article] Involvement of B Cells, Immunoglobulins, and Syk in the Pathogenesis of Abdominal Aortic Aneurysm (2018)
  • Author(s): Furusho Aya、Aoki Hiroki、Ohno‐Urabe Satoko、Nishihara Michihide、Hirakata Saki、Nishida Norifumi、Ito Sohei、Hayashi Makiko、Imaizumi Tsutomu、Hiromatsu Shinichi、Akashi Hidetoshi、Tanaka Hiroyuki、Fukumoto Yoshihiro
  • Journal Title: Journal of the American Heart Association Volume: 7 Issue: 6
  • DOI: 10.1161/jaha.117.007750
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection. (2018)
  • Author(s): Satoko Ohno-Urabe, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Hideo Yasukawa, Tsutomu Imaizumi, Hidetoshi Akashi, Hiroyuki Tanaka, Yoshihiro Fukumoto
  • Journal Title: Journal of the American Heart Association Volume: 7
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of B Cells, Immunoglobulins, and Syk in the Pathogenesis of Abdominal Aortic Aneurysm. (2018)
  • Author(s): Aya Furusho, Hiroki Aoki, Satoko Ohno-Urabe, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Tsutomu Imaizumi, Shinichi Hiromatsu, Hidetoshi Akashi, Hiroyuki Tanaka, Yoshihiro Fukumoto
  • Journal Title: Journal of the American Heart Association Volume: 7
  • Open Access
• [Journal Article] The role of IL-6 in pathogenesis of abdominal aortic aneurysm in mice (2017)
  • Author(s): Michihide Nishihara, Hiroki Aoki, Satoko Ohno, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Tsutomu Imaizumi, Yoshihiro Fukumoto
  • Journal Title: PLos ONE Volume: 12
  • Peer Reviewed / Open Access
• [Presentation] 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, Paris, France
  • 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, Paris, France
  • Int'l Joint Research
• [Presentation] he role of Spleen tyrosine kinase in human abdominal aortic aneurysm pathogenesis. (2019)
  • Author(s): R Kanamoto, H Aoki, A Furusho, H Otsuka, Y Shintani, S Tobinaga, S Hiromatsu, Y Fukumoto, H Tanaka
  • Organizer: ESC CONGRESS 2019, Paris, France
  • Int'l Joint Research
• [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: Boston
  • Int'l Joint Research
• [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: 第83回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] AK 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: 第83回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] Involvement of B cell/Syk Axis in Development of Abdominal Aortic Aneurysm (2018)
  • Author(s): Furusho A, Aoki H, Nishihara M, Ohno-Urabe S, Hirakata S, Nishida N, Ito S, Hayashi Y, Ito S, Hashimoto Y, Majima R, Fukumoto Y
  • Organizer: 第82回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] Involvement of Bcell/Syk Axis in Development of Abdominal Aortic Aneurysm (2018)
  • Author(s): A. Furusho, H. Aoki, M. Nishihara, S. Ohno, S. Hirakata,N. Nishida, S.Ito, M. Hayashi, Y. Hashimoto, R. Majima, Y. Fukumoto
  • Organizer: The 82nd Annual Scientific Meeting of the Japanese Circulation Society
  • Int'l Joint Research
• [Presentation] B Cells Promate the Progression of Aortic Dissection through a Proinflammatory Response (2017)
  • Author(s): A. Furusho, H. Aoki, S. Ohno, M. Nishihara, S Hirakarta, N. Nishida, S.Ito, M. Hayashi, H. Akashi, H. Tanaka, Y. Fukumoto
  • Organizer: The 81st Annual Scientific Meeting of the Japanese Circulation Society
  • Int'l Joint Research
• [Presentation] Involvement of B cell/Syk axis in developement of abdominal aortic aneurysm. (2017)
  • Author(s): A. Furusho, H. Aoki, S. Ohno, M. Nishihara, S Hirakarta, N. Nishida, S.Ito, M. Hayashi, H. Akashi, H. Tanaka, Y. Fukumoto
  • Organizer: European Society of Cardiology Congress 2017
  • Int'l Joint Research