Elucidation of the protective role of vascular smooth muscle STAT3 in aortic dissociation

• Project/Area Number: 16K10669
• 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: Hirakata Saki 久留米大学, 医学部, 助教 (60597425)
• Co-Investigator(Kenkyū-buntansha): 田中 啓之 久留米大学, 医学部, 教授 (70197466)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 大動脈解離 / 血管 / 分子生物学 / 大血管 / 外科 / 循環器・高血圧

Outline of Final Research Achievements

Aortic dissection (AD) is an acute destruction of aortic wall, which is reportedly promoted by inflammatory response. We investigated the role of smooth muscle Socs3, a negative regulator of Jak/Stat signaling, in AD pathogenesis using a mouse model with β-aminopropionitril and angiotensin II infusion. Genetic deletion of Socs3 specifically in smooth muscle cells resulted in chronic inflammatory response of the aortic wall, which was associated with increase in fibroblasts, reinforced aortic tensile strength and less severe tissue destruction. Although acute inflammatory response is detrimental to AD, smooth muscle-regulated inflammatory response seemed protective against AD.

Academic Significance and Societal Importance of the Research Achievements

大動脈解離は、社会的な影響が重大な50代男性に好発する致命的な疾患であるにもかかわらず、外科的治療以外にその進行を阻止するような積極的治療法はない。病態もほとんど未解明であるため病状を把握することも困難であるのが現状である。本研究の結果から、従来大動脈解離にとって破壊を促進する有害なものとされた炎症が、反対に保護的な役割も担っている可能性があることがわかり、その中心となるのが平滑筋細胞であることも発見した。具体的に線維芽細胞の増加、大動脈壁強度の増強により組織破壊の重症化が抑制されていることも明らかとなったことから、これまで進んでいなかった解離進行阻止療法の開発につながる重要な知見となった。

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] Focal Adhision Kinase Promotes the 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
  • Int'l Joint Research
• [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
  • 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
  • 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
  • Int'l Joint Research
• [Presentation] Focal adhision 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: The 2nd JCS Council Forum on Basic CardioVascular 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
• [Presentation] Molecular Pathology of Aortic Dissection. (2018)
  • Author(s): 青木浩樹, 大野聡子, 平方佐季
  • Organizer: 日本顕微鏡学会第74回学術講演会
  • Invited
• [Presentation] STAT3 in Smooth Muscle Cells Prevents Progression of Aortic Dissection by Reinforcing the Physical Strength of Aortic Walls (2018)
  • Author(s): Saki Hirakata, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Aya Furusho, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Youhei Hashimoto, Ryohei Majima, Yoshihiro Fukumoto
  • Organizer: 第82回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] High Salt and IL-17 Synergistically Worsen Aortic Dissection by Dysregulation of Extracellular Matrix (2018)
  • Author(s): Norifumi Nishida, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Aya Furusho, Saki Hirakata, Sohei Ito, Makiko Hayashi, Youhei Hashimoto, Ryohei Majima, Yoshihiro Fukumoto
  • Organizer: 第82回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] Involvement of B Cell/Syk in the Development of Abdominal Aortic Aneurysm (2018)
  • Author(s): 古荘 文、西原 通秀、大野 聡子、平方 佐季、西田 憲史、伊東 壮平、林 真貴子、橋本 洋平、眞島 涼平、福本 義弘
  • Organizer: 第82回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] Macrophage Stat3 Exacerbates Aortic Dissection through Dysregulated Differentiation of Macrophages and Smooth Muscle Cells (2018)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Youhei Hashimoto, Ryohei Majima, Yoshihiro Fukumoto
  • Organizer: 第82回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] MRTF-A Mediates Development of Aortic Dissection Through Aortic Smooth Muscle Cell Apoptosis and Inflammatory Response (2018)
  • Author(s): Sohei Ito, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Aya Furusho, Saki Hirakata, Norifumi Nishida, Makiko Hayashi, Youhei Hashimoto, Koichiro Kuwahara, Yoshihiro Fukumoto
  • Organizer: 第82回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] STAT3 Determines Differentiation of Macrophages and Progression of Aortic Dissection (2017)
  • Author(s): S. Ohno, H. Aoki, M. Nishihara, A. Furusho, S. Hirakata, N. Nishida, S. Ito, M. Hayashi, H. Akashi, H. Tanaka, Y. Fukumoto
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂、金沢市、石川県
  • 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, Sohei Ito, Makiko Hayashi, Hiroyuki Tanaka, Yoshihiro Fukumoto
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂、金沢市、石川県
  • Year and Date: 2017-03-17
• [Presentation] High Salt Activates NFkB Pathway and Causes Worsening of Aortic Dissection via IL-17 Pathway (2017)
  • Author(s): Norifumi Nishida, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Aya Furusho, Saki Hirakata, Sohei Ito, Makiko Hayashi, Hiroyuki Tanaka, Yoshihiro Fukumoto
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂、金沢市、石川県
  • Year and Date: 2017-03-17
• [Presentation] Myocardin-related Transcription Factor-A is Required for Development of Aortic Dissection (2017)
  • Author(s): S. Ito, H. Aoki, S. Ohno, M. Nishihara, A. Furusho, S. Hirakata, N. Nishida, M. Hayashi, Yoichiro Kuwahara, Y. Fukumoto
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂、金沢市、石川県
  • Year and Date: 2017-03-17
• [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. Hirakata, N. Nishida, S. Ito, H. Akashi, H. Tanaka, Y. Fukumoto
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂、金沢市、石川県
  • Year and Date: 2017-03-17
• [Presentation] Macrophage STAT3 activation promotes aortic dissection via imbalance of tissue destruction and protection. (2016)
  • Author(s): S. Ohno, H. Aoki, M. Nishihara, A. Furusho, S. Hirakata, N. Nishida, S. Ito, M. Hayashi, H. Akashi, H. Tanaka, Y. Fukumoto
  • Organizer: American Heart Association Scientific Sessions 2016
  • Place of Presentation: New Orleans, Louisiana, USA
  • 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): S. Ito, H. Aoki, S. Ohno, M. Nishihara, A. Furusho, S. Hirakata, N. Nishida, M. Hayashi, Yoichiro Kuwahara, Y. Fukumoto
  • Organizer: American Heart Association Scientific Sessions 2016
  • Place of Presentation: New Orleans, Louisiana, USA
  • Year and Date: 2016-11-12
  • 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, Sohei Ito, Makiko Hayashi, Hiroyuki Tanaka, Yoshihiro Fukumoto
  • Organizer: ESC CONGRESS 2016
  • Place of Presentation: Rome, Italy
  • Year and Date: 2016-08-27
  • 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, Michihide Nishihara, Satoko Ohno, Aya Furusho, Saki Hirakata, Sohei Ito, Makiko Hayashi, Hiroyuki Tanaka, Yoshihiro Fukumoto
  • Organizer: ESC CONGRESS 2016
  • Place of Presentation: Rome, Italy
  • 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, Sohei Ito, Makiko Hayashi, Hiroyuki Tanaka, Yoshihiro Fukumoto
  • Organizer: ESC CONGRESS 2016
  • Place of Presentation: Rome, Italy
  • 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, Sohei Ito, Makiko Hayashi, Hiroyuki Tanaka, Yoshihiro Fukumoto
  • Organizer: ESC CONGRESS 2016
  • Place of Presentation: Rome, Italy
  • Year and Date: 2016-08-27
  • Int'l Joint Research
• [Book] Mouse Model of Abdominal Aortic Aneurysm Induced by CaCl2 (2016)
  • Author(s): Aoki H, Ohno S, Furusho A, Nishihara M, Nishida N, Hirakata S, Yoshimura K
  • Total Pages: 16
  • Publisher: Mouse Models of Vascular Diseases. M. Sata, Springer Japan