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

• Project/Area Number: 16K19973
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular surgery
• Research Institution: Kurume University
• Principal Investigator: NISHIDA Norifumi 久留米大学, 医学部, 助教 (50624508)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 大動脈解離 / 塩分過剰 / IL-17 / 細胞外マトリックス

Outline of Final Research Achievements

In this project, we investigated the mechanism of worsening aortic dissection by high salt intake and the involvement of IL-17. High salt induced IL-17 receptor expression without affecting plasma IL-17, and activated NFkB in aorta in an IL-17-dependent manner, suggesting the increase the sensitivity of aortic tissue to IL-17. In addition, deletion of IL-17 gene showed higher activity of Smad2, upregulation of ECM genes, and increase in medial collagen fibers in aorta. Interestingly, high salt induced expression of Smad7, a negative regulator of Smad signaling, and suppressed Smad2 activation in an IL-17-dependent manner. We propose that high salt and IL-17 synergistically dysregulate ECM metabolism in aorta to exacerbate AD.

Research Products

• [Journal Article] Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection (2018)
  • Author(s): Ohno‐Urabe Satoko、Aoki Hiroki、Nishihara Michihide、Furusho Aya、Hirakata Saki、Nishida Norifumi、Ito Sohei、Hayashi Makiko、Yasukawa Hideo、Imaizumi Tsutomu、Akashi Hidetoshi、Tanaka Hiroyuki、Fukumoto Yoshihiro
  • Journal Title: Journal of the American Heart Association Volume: 7 Issue: 2
  • DOI: 10.1161/jaha.117.007389
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] The role of IL-6 in pathogenesis of abdominal aortic aneurysm in mice (2017)
  • Author(s): Nishihara Michihide、Aoki Hiroki、Ohno Satoko、Furusho Aya、Hirakata Saki、Nishida Norifumi、Ito Sohei、Hayashi Makiko、Imaizumi Tsutomu、Fukumoto Yoshihiro
  • Journal Title: PLOS ONE Volume: 12 Issue: 10 Pages: e0185923-e0185923
  • DOI: 10.1371/journal.pone.0185923
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] High Salt Activates NFkB Pathway and Causes Worsening of Aortic Dissection via IL-17 Pathway (2017)
  • Author(s): Norifumi Nishida, Hiroki Aoki, Satoko Ohno, Michihide Nishihara, Aya Furusho, Saki Hirakata, Makiko Hayashi, Sohei Ito, Hideo Yasukawa, Yoshihiro Fukumoto
  • Organizer: The 81st Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 金沢フォーラス(石川県金沢市)
  • Year and Date: 2017-03-17
• [Presentation] STAT3 Determines Differentiation of Macrophages and Progression of Aortic Dissection (2017)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Makiko Hayashi, Sohei Ito, Yoshihiro Fukumoto
  • Organizer: The 81st Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 金沢市教育プラザ此花 体育館(石川県金沢市)
  • Year and Date: 2017-03-17
• [Presentation] B cells Promote the Progression of Aortic Dissection through a proinflammatory response (2017)
  • Author(s): Aya Furusho, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Saki Hirakata, Norifumi Nishida, Makiko Hayashi, Sohei Ito, Yoshihiro Fukumoto
  • Organizer: The 81st Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 金沢市教育プラザ此花 体育館(石川県金沢市)
  • Year and Date: 2017-03-17
• [Presentation] Central Role of mTOR Pathway in Molecular Pathogenesis of Aortic Dissection (2017)
  • Author(s): Makiko Hayashi, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Yoshihiro Fukumoto
  • Organizer: The 81st Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 金沢市教育プラザ此花 体育館(石川県金沢市)
  • Year and Date: 2017-03-17
• [Presentation] Myocardin-related Transcription Factor-A is Required for Development of Aortic Dissection (2017)
  • Author(s): Sohei Ito, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Aya Furusho, Saki Hirakata, Norifumi Nishida, Makiko Hayashi, Yoshihiro Fukumoto
  • Organizer: The 81st Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: ヴィサージュ(石川県金沢市)
  • Year and Date: 2017-03-17
• [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
• [Presentation] Macrophage Socs3 is the Determinant for the Development of Aortic Dissection (2016)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Makiko Hayashi, Sohei Ito, Yoshihiro Fukumoto
  • Organizer: American Heart Association Scientific Session 2016
  • Place of Presentation: ニューオーリンズ (アメリカ合衆国)
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Myocardin-Related Transcription Factor-A is Required for Development of Aortic Dissection (2016)
  • Author(s): Sohei Ito, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Aya Furusho, Saki Hirakata, Norifumi Nishida, Makiko Hayashi, Yoshihiro Fukumoto
  • Organizer: American Heart Association Scientific Session 2016
  • Place of Presentation: ニューオーリンズ (アメリカ合衆国)
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Molecular mechanism of worsening aortic dissection by high salt through IL-17 pathway. (2016)
  • Author(s): Norifumi Nishida, Hiroki Aoki, Satoko Ohno, Michihide Nishihara, Aya Furusho, Saki Hirakata, Makiko Hayashi, Sohei Ito, Hideo Yasukawa, Yoshihiro Fukumoto
  • Organizer: European Society of Cardiology Congress 2016
  • Place of Presentation: ローマ (イタリア)
  • Year and Date: 2016-08-27
  • Int'l Joint Research
• [Presentation] Macrophage STAT3 activation promotes aortic dissection via imbalance of tissue destruction and protection (2016)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Makiko Hayashi, Sohei Ito, Yoshihiro Fukumoto
  • Organizer: European Society of Cardiology Congress 2016
  • Place of Presentation: ローマ (イタリア)
  • Year and Date: 2016-08-27
  • Int'l Joint Research
• [Presentation] B cells promote abdominal aortic aneurysm and aortic dissection through proinflammatory function of immunoglobulins (2016)
  • Author(s): Aya Furusho, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Saki Hirakata, Norifumi Nishida, Makiko Hayashi, Sohei Ito, Yoshihiro Fukumoto
  • Organizer: European Society of Cardiology Congress 2016
  • Place of Presentation: ローマ (イタリア)
  • Year and Date: 2016-08-27
  • Int'l Joint Research
• [Presentation] STAT3 in vascular smooth muscle cells protects aorta from dissection by reinforcing extracellular matrix (2016)
  • Author(s): Saki Hirakata,Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Aya Furusho, Norifumi Nishida, Makiko Hayashi, Sohei Ito, Yoshihiro Fukumoto
  • Organizer: European Society of Cardiology Congress 2016
  • Place of Presentation: ローマ (イタリア)
  • Year and Date: 2016-08-27
  • Int'l Joint Research