Molecular mechanism of worsening aortic dissection by high salt via IL-17 pathway

2017 Fiscal Year Annual Research Report

• Project/Area Number: 16K19973
• Research Institution: Kurume University
• Principal Investigator: 西田 憲史 久留米大学, 医学部, 助教 (50624508)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Keywords: 大動脈解離 / 塩分過剰 / IL-17 / 細胞外マトリックス

Outline of Annual Research Achievements

大動脈解離は突然発症する致死的疾患であるが、病態は不明で予防方法は存在せず、外科的手術以外の治療法もない。大動脈解離は最近増加傾向にあり、突然死による社会的損失も大きいことから、その予防と治療法の開発は解決すべき重要課題である。
申請者の予備的検討から心血管疾患の危険因子である塩分過剰が大動脈解離を増悪させ、そのメカニズムの中心にIL-17と細胞外マトリックス(ECM)が関与している可能性が示された。塩分過剰が大動脈解離を増悪させるメカニズムを解明し、治療戦略を開発することを目的に研究を進めた。
マウスへの塩分負荷は大動脈組織のIL-17Aを変化させずIL-17受容体を増加させNFkBを活性化したことから、塩分過剰がL-17感受性を高める可能性が示唆された。マウス大動脈解離モデルの網羅的遺伝子解析では、大動脈解離刺激はECM遺伝子群に大きな影響を及ぼし、IL-17ノックアウトはECM遺伝子群の発現パターンを大きく変化させた。
野生型マウス大動脈において塩分負荷はTGFβ経路の抑制分子Smad7の発現を亢進させる一方、IL-17ノックアウトマウスの大動脈ではSmad7の発現低下とSmad2活性亢進が認められた。マウス大動脈組織のピクロシリウスレッド染色では、野生型マウスと比較してIL-17ノックアウトマウスでは中膜コラーゲン線維が増加していた。TGFβ経路はECM代謝制御因子であることから、IL-17はTGF-β経路を介してECM代謝を抑制すると考えられた。
以上より、塩分過剰はIL-17を介してECM代謝異常、大動脈解離増悪を引き起こすことが示された。塩分過剰/IL-17経路は大動脈解離の有効な予防および治療ターゲットとなる可能性が高い。今後は、塩分過剰によるTGF-β経路への影響を引き起こすメカニズムの解明を行い、さらなる病態解明と予防・治療ターゲットの同定を目指す。

Research Products

• [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: Jornal of American Heart Association Volume: 7(2) Pages: e007389
  • DOI: 10.1161/JAHA.117.007389.
  • 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: Jornal of American Heart Association Volume: 7(6) Pages: e007750
  • DOI: 10.1161/JAHA.117.007750.
  • Peer Reviewed / 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(10) Pages: e0185923
  • DOI: 10.1371/journal.pone.0185923. eCollection 2017.
  • Peer Reviewed / Open Access
• [Presentation] High Salt and IL-17 Synergistically Worsen Aortic Dissection by Dysregulation pf Extracellular Matrix (2018)
  • Author(s): N. Nishida, H. Aoki, S. Ohno, M. Nishihara, A. Furusho, S Hirakarta, S.Ito, M. Hayashi, H. Yasukawa, Y. Fukumoto
  • Organizer: The 82nd Annual Scientific Meeting of the Japanese Circulation Society
• [Presentation] STAT3 in Smooth Muscle Cells Prevents Progression of Aortic Dissection by Reinforcing the Physical Strength of Aortic Walls (2018)
  • Author(s): S. Hirakata, H. Aoki, M. Nishihara, S. Ohno, A. Furusho, N. Nishida, S.Ito, M. Hayashi, Youhei Hashimoto, Ryohei Majima, Y. Fukumoto
  • Organizer: The 82nd Annual Scientific Meeting of the Japanese Circulation Society
• [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
• [Presentation] MRTF-A Mediates Development of Aortic Dissection Through Aortic Smooth Muscle Cell Apotosis and Inflammatory Response (2018)
  • Author(s): S.Ito, H. Aoki, S. Ohno, M. Nishihara, A. Furusho, S. Hirakata,N. Nishida, M. Hayashi, Y. Hashimoto, K. Kuwahara, Y. Fukumoto
  • Organizer: The 82nd Annual Scientific Meeting of the Japanese Circulation Society
• [Presentation] Macrophage Stat3 Excerbates Aortic Dissection through Dysregulated Differetiation of Macrophages and Smooth Muscle Cells (2018)
  • Author(s): S. Ohno, H. Aoki, M. Nishihara, A. Furusho, S. Hirakata,N. Nishida, S.Ito, M. Hayashi, Y. Fukumoto
  • Organizer: The 82nd Annual Scientific Meeting of the Japanese Circulation Society
• [Presentation] Synergistic effect of high salt and IL-17 worsens aortic dissection by dysregulation of extracellular matrix. (2017)
  • Author(s): N. Nishida, H. Aoki, S. Ohno, M. Nishihara, A. Furusho, S Hirakarta, S.Ito, M. Hayashi, H. Yasukawa, Y. Fukumoto
  • Organizer: European Society of Cardiology Congress 2017
  • Int'l Joint Research
• [Presentation] 塩分過剰による大動脈解離の増悪にはIL-17が関与する：マウス解離モデルを用いた検討 (2017)
  • Author(s): 西田憲史、青木浩樹、大野聡子、西原通秀、古荘文、平方佐季、林真貴子、伊東壮平、福本義弘
  • Organizer: 第53回高血圧関連疾患モデル学会学術総会
• [Presentation] Macrophage Stat3 promptes progression of aortic dissection via M1 differentiation and smooth muscle dedifferentiation (2017)
  • Author(s): S. Ohno, H. Aoki, M. Nishihara, A. Furusho, 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
• [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
• [Presentation] Central role of mTOR pathway in molecular pathogenesis of aortic dissection. (2017)
  • Author(s): M. Hayashi, H. Aoki, S. Ohno, M. Nishihara, A. Furusho, S Hirakarta, N. Nishida, S.Ito, Y. Fukumoto
  • Organizer: European Society of Cardiology Congress 2017
  • Int'l Joint Research
• [Presentation] Myocardin-related transcription factor-A is required for developement of aortic dissection. (2017)
  • Author(s): S.Ito, H. Aoki, S. Ohno, M. Nishihara, A. Furusho, S Hirakarta, N. Nishida, M. Hayashi, Y. Fukumoto
  • Organizer: European Society of Cardiology Congress 2017
  • Int'l Joint Research
• [Presentation] MTOR Promotes Aortic Dissection Trough Cell Proliferation (2017)
  • Author(s): M. Hayashi, H. Aoki, S. Ohno, M. Nishihara, A. Furusho, S Hirakarta, N. Nishida, S.Ito, Y. Fukumoto
  • Organizer: American Heart Association Scientific Session 2017
  • Int'l Joint Research
• [Presentation] MRTF-A Mediates Developement of Aortic Dissection Through Aortic Smooth Muscle Cell Apotosis and Inflammation Response (2017)
  • Author(s): S.Ito, H. Aoki, S. Ohno, M. Nishihara, A. Furusho, S Hirakarta, N. Nishida, M. Hayashi, Y. Fukumoto
  • Organizer: American Heart Association Scientific Session 2017
  • Int'l Joint Research
• [Presentation] mTOR promotes aortic dissection through cell proliferation (2017)
  • Author(s): 林真貴子、青木浩樹、大野聡子、西原通秀、平方佐季、古荘文、西田憲史、伊東壮平、橋本洋平、眞島涼平、福本義弘
  • Organizer: 第123回日本循環器学会九州地方会
• [Presentation] MRTF-Aは炎症応答、血管平滑筋細胞のアポトーシスを介して大動脈解離を引き起こす (2017)
  • Author(s): 伊東壮平、青木浩樹、大野聡子、西原通秀、平方佐季、古荘文、西田憲史、林真貴子、橋本洋平、眞島涼平、福本義弘
  • Organizer: 第123回日本循環器学会九州地方会