A novel therapeutic strategy for aortic dissection

• Project/Area Number: 16H05428
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular surgery
• Research Institution: Kurume University
• Principal Investigator: AOKI hiroki 久留米大学, 循環器病研究所, 教授 (60322244)
• Co-Investigator(Kenkyū-buntansha): 田中 啓之 久留米大学, 医学部, 教授 (70197466) ; 大野 聡子 久留米大学, 医学部, 助教 (80569418) ; 古荘 文 久留米大学, 医学部, 助教 (80597427)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2016: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 大動脈 / 細胞増殖 / 炎症 / 組織破壊 / 組織保護 / 大動脈解離 / mTOR / ラパマイシン / 細胞周期 / 平滑筋 / 大血管外科学 / mTORシグナル / トランスレーショナルリサーチ / 循環器・高血圧 / 細胞外マトリックス

Outline of Final Research Achievements

Aortic dissection (AD) is a fatal disease that occurs suddenly without preceding clinical signs or symptoms. In the current study, we demonstrated that rapamycin-sensitive mTOR pathway governs cell proliferation of aortic wall cells in response to AD-inducing stimuli. Suppression of mTOR pathway by rapamycin completely prevented the AD development and progression after AD onset. Mechanistically, rapamycin treatment resulted in the inhibition of cell proliferation, and activation Stat3 in aortic wall medial smooth muscle cells. In turn, activation of smooth muscle Stat3 protected aortic tissue partly by activating adventitial fibroblast and deposition of collagen fibers. Deciphering the molecular mechanism of AD would be essential in developing the diagnostic and therapeutic strategies for this fatal disease.

Academic Significance and Societal Importance of the Research Achievements

これまで大動脈解離がどのように起こり、進行するかはよく分かっていなかった。今回の研究から、大動脈解離が起こる根本的な仕組みの一端が明らかになった。動物モデルでは効果的な予防・治療法が示され、ヒト大動脈でも動物モデルと同様の反応が起こることが示された。今回の研究からは、血圧や血流で大きなストレスを受ける大動脈が100年間持ちこたえる仕組みが明らかになり、その異常としての大動脈解離の仕組みの一部が解き明かされてきた。このような発見は、予防法や治療法の開発、病気を起こす可能性がある人の発見や、起こった後の診断法の開発に役立つことが期待される。

Research Products

• [Journal Article] Activation of the AKT Pathway in the Ascending Aorta With Bicuspid Aortic Valve (2018)
  • Author(s): Hirata, Y. Aoki, H. Shojima, T. Takagi, K. Takaseya, T. Akasu, K. Tobinaga, S. Fukumoto, Y. Tanaka, H.
  • Journal Title: Circulation Journal Volume: 82 Issue: 10 Pages: 2485-2492
  • DOI: 10.1253/circj.CJ-17-1465
  • NAID: 130007490212
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2018-09-25
  • Peer Reviewed / Open Access
• [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] Cytokine Profile of Human Abdominal Aortic Aneurysm: Involvement of JAK/STAT Pathway (2018)
  • Author(s): Ohno T, Aoki H, Ohno S, Nishihara M, Furusho A, Hiromatsu S, Akashi H, Fukumoto Y, Tanaka H.
  • Journal Title: Annals of Vascular Diseases Volume: 11 Issue: 1 Pages: 84-90
  • DOI: 10.3400/avd.oa.17-00086
  • NAID: 130006549626
  • ISSN: 1881-641X, 1881-6428
  • Peer Reviewed / Open Access
• [Journal Article] Propagation-based phase-contrast synchrotron imaging of aortic dissection in mice: from individual elastic lamella to 3D analysis (2018)
  • Author(s): Logghe G, Trachet B, Aslanidou L, Villaneuva-Perez P, De Backer J, Stergiopulos N, Stampanoni M, Aoki H, Segers P
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 2223-2223
  • DOI: 10.1038/s41598-018-20673-x
  • 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] Characterization of SMAD2 Activation in Human Thoracic Aortic Aneurysm (2018)
  • Author(s): Fukuda H, Aoki H, Yoshida S, Tobinaga S, Otsuka H, Shojima T, Takagi K, Fukumoto Y, Akashi H, Kato S, Tanaka H
  • Journal Title: Annals of Vascular Diseases Volume: 11 Issue: 1 Pages: 112-119
  • DOI: 10.3400/avd.oa.17-00114
  • NAID: 130006549680
  • ISSN: 1881-641X, 1881-6428
  • Peer Reviewed / Open Access
• [Journal Article] Loss of MURC/Cavin-4 induces JNK and MMP-9 activity enhancement in vascular smooth muscle cells and exacerbates abdominal aortic aneurysm (2017)
  • Author(s): 13.Miyagawa K, Ogata T, Ueyama T, Kasahara T, Nakanishi N, Naito D, Taniguchi T, Hamaoka T, Maruyama N, Nishi M, Kimura T, Yamada H, Aoki H, Matoba S
  • Journal Title: Biochem Biophys Res Commun Volume: 487 Issue: 3 Pages: 587-593
  • DOI: 10.1016/j.bbrc.2017.04.096
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genetic Ablation of MicroRNA-33 Attenuates Inflammation and Abdominal Aortic Aneurysm Formation via Several Anti-Inflammatory Pathways. (2017)
  • Author(s): Nakao T, Horie T, Baba O, Nishiga M, Nishino T, Izuhara M, Kuwabara Y, Nishi H, Usami S, Nakazeki F, Ide Y, Koyama S, Kimura M, Sowa N, Ohno S, Aoki H, Hasegawa K, Sakamoto K, Minatoya K, Kimura T, Ono K.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 37 Issue: 11 Pages: 2161-2170
  • DOI: 10.1161/atvbaha.117.309768
  • Peer Reviewed / Open Access
• [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 M, 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 M, 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] The role of spleen tyrosine kinase in inflammation-related pathways in human abdominal aortic aneurysm tissue (2018)
  • Author(s): Kanamoto R, Furusho A, Aoki H, Otsuka H, Shintani Y, Hiromatsu S, Fukumoto Y and Tanaka H
  • 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 M, 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 M, Hashimoto Y, Majima R, Kuwahara K, Fukumoto Y
  • Organizer: ESC Congress 2018
  • Int'l Joint Research
• [Presentation] High salt and IL-17 synergistically worsen aortic dissection by dysregulation of extracellular matrix. (2018)
  • Author(s): Nishida N, Aoki H, Nishihara M, Ohno-Urabe S, Furusho A, Hirakata S, Ito S, Hayashi M, Hashimoto Y, Majima R, Fukumoto Y
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Stat3 in smooth muscle cells prevent the progression of AD by reinforcing the physical strength of aortic walls (2018)
  • Author(s): Hirakata S, Aoki H, Nishihara M, Ohno-Urabe S, Furusho A, Nishida N, Ito S, Hayashi M, Hashimoto Y, Majima R, Fukumoto Y
  • Organizer: 第82回日本循環器学会学術集会
• [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 M, Hashimoto Y, Majima R, Fukumoto Y
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Macrophage Stat3 Exacerbates Aortic Dissection through Dysregulated Differentiation of Macrophages and Smooth Muscle Cells (2018)
  • Author(s): Ohno-Urabe S, Aoki H, Nishihara M, Furusho A, Hirakata S, Nishida N, Ito S, Hayashi M, Hashimoto Y, Majima R, Fukumoto Y
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] MRTF-A Mediates Development of Aortic Dissection Through Aortic Smooth Muscle Cell Apoptosis and Inflammatory Response (2018)
  • Author(s): Ito S, Aoki H, Nishihara M, Ohno-Urabe S, Furusho A, Hirakata S, Nishida N, Hayashi M, Hashimoto Y, Majima R, Fukumoto Y
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] mTOR regulates development and progression of aortic dissection (2018)
  • Author(s): Hayashi M, Aoki H, Nishihara M, Ohno-Urabe S, Furusho A, Hirakata S, Nishida N, Ito S, Hashimoto Y, Majima R, Kuwahara K, Fukumoto Y
  • Organizer: The 1st JCS Council Forum on Basic CardioVascular Research
  • Int'l Joint Research
• [Presentation] Myocardin-related transcription factor-A promotes development of aortic dissection (2018)
  • Author(s): Ito S, Aoki H, Nishihara M, Ohno-Urabe S, Furusho A, Hirakata S, Nishida N, Hayashi M, Hashimoto Y, Majima R, Kuwahara K, Fukumoto Y
  • Organizer: The 1st JCS Council Forum on Basic CardioVascular Research
  • 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 M, Ito S, Ohno-Urabe S, Furusho A, Nishida N, Hirakata S, Fukumoto Y
  • Organizer: The 2nd JCS Council Forum on Basic CardioVascular Research
  • Int'l Joint Research
• [Presentation] The role of Syk in pathogenesis of aortic dissection (2018)
  • Author(s): Hashimoto Y, Aoki H, Majima R, Hayashi M, Ito S, Ohno-Urabe S, Furusho A, Nishida N, Hirakata S, Fukumoto Y
  • Organizer: The 2nd JCS Council Forum on Basic CardioVascular Research
  • Int'l Joint Research
• [Presentation] 腹部大動脈瘤と大動脈解離の病態 (2018)
  • Author(s): 青木浩樹
  • Organizer: 中性脂肪学会第2回学術集会
  • Invited
• [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] 大動脈疾患の分子病態：オーバービュー (2018)
  • Author(s): 青木浩樹,
  • Organizer: 第59回日本脈管学会総会
  • Invited
• [Presentation] 大動脈解離の分子病態における mTOR の役割 (2018)
  • Author(s): 堀真貴子
  • Organizer: 第59回日本脈管学会総会
  • Invited
• [Presentation] MRTF-A Mediates Development of Aortic Dissection Through Aortic Smooth Muscle Cell Apoptosis and Inflammatory Response (2018)
  • Author(s): Sohei Ito, Hiroki Aoki, Satoko Ohno, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Makiko Hayashi, Koichiro Kuwahara, Yoshihiro Fukumoto
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Macrophage Stat3 Exacerbates Aortic Dissection through Dysregulated Differentiation of Macrophages and Smooth Muscle (2018)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Koichiro Kuwahara, Yoshihiro Fukumoto
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Involvement of B cell/Syk axis in Development of Abdominal Aortic Aneurysm (2018)
  • Author(s): Aya Furusho, Hiroki Aoki, Satoko Ohno, Michihide Nishihara, Saki Hirakata, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Koichiro Kuwahara, Yoshihiro Fukumoto
  • Organizer: 第82回日本循環器学会学術集会
• [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, Satoko Ohno, Michihide Nishihara, Aya Furusho, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Koichiro Kuwahara, Yoshihiro Fukumoto
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] High Salt and IL-17 Synergistically Worsen Aortic Dissection by Dysregulation of Extracellular Matrix (2018)
  • Author(s): Norifumi Nishida, Hiroki Aoki, Satoko Ohno, Michihide Nishihara, Aya Furusho, Saki Hirakata, Sohei Ito, Makiko Hayashi, Koichiro Kuwahara, Yoshihiro Fukumoto
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Myocardin-related transcription factor-A is required for development of aortic dissection (2017)
  • Author(s): Sohei Ito, Hiroki Aoki, Satoko Ohno, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Makiko Hayashi, Koichiro Kuwahara, Yoshihiro Fukumoto
  • Organizer: ESC Congress 2017
  • Int'l Joint Research
• [Presentation] MRTF-A Mediates Development of Aortic Dissection Through Aortic Smooth Muscle Cell Apoptosis and Inflammatory Response (2017)
  • Author(s): Sohei Ito, Hiroki Aoki, Satoko Ohno, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Makiko Hayashi, Koichiro Kuwahara, Yoshihiro Fukumoto
  • Organizer: American Heart Association Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] mTOR Promotes Aortic Dissection Through Cell Proliferation (2017)
  • Author(s): Makiko Hayashi, Hiroki Aoki, Satoko Ohno, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Yoshihiro Fukumoto
  • Organizer: American Heart Association Scientific Sessions 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 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, 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, H. Akashi, H. Tanaka, Y. Fukumoto
  • Organizer: American Heart Association Scientific Sessions 2016
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [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: ESC Congress Rome 2016
  • Place of Presentation: Rome, Italy
  • 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): S. Hirakata, H. Aoki, M. Nishihara, S. Ohno, A. Furusho, N. Nishida, S. Ito, M. Hayashi, H. Tanaka, Y. Fukumoto
  • Organizer: ESC Congress Rome 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): N. Nishida, H. Aoki, S. Ohno, M. Nishihara, A. Furusho, S. Hirakata, M. Hayashi, S. Ito, H. Yasukawa, Y. Fukumoto
  • Organizer: ESC Congress Rome 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): A. Furusho, H. Aoki, M. Nishihara, S. Ohno, S. Hirakata, N. Nishida, S. Ito, M. Hayashi, H. Akashi, H. Tanaka, Y. Fukumoto
  • Organizer: ESC Congress Rome 2016
  • Place of Presentation: Rome, Italy
  • Year and Date: 2016-08-27
  • Int'l Joint Research
• [Book] Mouse Models of Vascular Diseases (2016)
  • Author(s): Aoki H, Ohno S, Furusho A, Nishihara M, Nishida N, Hirakata S, Yoshimura K
  • Total Pages: 296
  • Publisher: Springer Japan