Deciphering molecular pathogenesis of aortic dissection: the role of stress sensor molecules

• Project/Area Number: 26670621
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• 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): KANAYAMA Shuri 昭和大学, 医学部, 講師 (10338535) ; TANAKA Hiroyuki 久留米大学, 医学部, 教授 (70197466)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 大動脈解離 / ストレス応答 / 遺伝子発現 / 機械的ストレス / 循環器・高血圧 / シグナル伝達 / 細胞・組織 / 生体分子 / 発現制御

Outline of Final Research Achievements

Aortic dissection is a medical emergency, in which patients frequently suffer from a sudden death. Currently, no specific non-surgical therapy is available for aortic dissection, because the etiology and pathogenesis is largely unknown. In this study we demonstrated that MRTF-A, an intracellular stress sensor, translates the mechanical and humoral stress to the tissue destructive response that eventually causes aortic dissection. MRTF-A inhibitor effectively prevented the development of aortic dissection, showing that MRTF-A is a promising therapeutic target.

Research Products

• [Journal Article] Taking Control of the Time Bomb in Abdominal Aortic Aneurysm (2016)
  • Author(s): Aoki, H.
  • Journal Title: Circulation Journal Volume: 80 Issue: 2 Pages: 314-315
  • DOI: 10.1253/circj.CJ-15-1350
  • NAID: 130005120884
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] 大動脈瘤の分子病態機序 (2015)
  • Author(s): 青木浩樹
  • Journal Title: 循環器専門医 Volume: 23 Pages: 3-7
• [Journal Article] Inhibitory effect of statins on inflammation-related pathways in human abdominal aortic aneurysm tissue (2015)
  • Author(s): Yoshimura, K. Nagasawa, A. Kudo, J. Onoda, M. Morikage, N. Furutani, A. Aoki, H. Hamano, K.
  • Journal Title: International journal of molecular sciences Volume: 16 Issue: 5 Pages: 11213-28
  • DOI: 10.3390/ijms160511213
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma (2015)
  • Author(s): Son, BK
  • Journal Title: Nat Commun Volume: 6 Issue: 1 Pages: 6994-6994
  • DOI: 10.1038/ncomms7994
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Fountain of Youth in the Aorta (2015)
  • Author(s): Aoki, H.
  • Journal Title: Circulation Journal Volume: 79 Issue: 7 Pages: 1439-1440
  • DOI: 10.1253/circj.CJ-15-0563
  • NAID: 130005083968
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Inflammasome activation by mitochondrial oxidative stress in macrophages leads to the development of angiotensin II-induced aortic aneurysm (2014)
  • Author(s): Usui F, Shirasuna K, Kimura H, Tatsumi K, Kawashima A, Karasawa T, Yoshimura K, Aoki H, Tsutsui H, Noda T, Sagara J, Taniguchi S, Takahashi M
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 35 Issue: 1 Pages: 127-136
  • DOI: 10.1161/atvbaha.114.303763
  • Peer Reviewed / Open Access
• [Journal Article] BMP type I receptor inhibition attenuates endothelial dysfunction in mice with chronic kidney disease (2014)
  • Author(s): Kajimoto, H. Kai, H. Aoki, H. Uchiwa, H. Aoki, Y. Yasuoka, S. Anegawa, T. Mishina, Y. Suzuki, A. Fukumoto, Y. Imaizumi, T.
  • Journal Title: Kidney international Volume: 87 Issue: 1 Pages: 128-36
  • DOI: 10.1038/ki.2014.223
  • Peer Reviewed
• [Journal Article] Tenascin C protects aorta from acute dissection in mice. (2014)
  • Author(s): Kimura, T., K. Shiraishi, A. Furusho, S. Ito, S. Hirakata, N. Nishida, K. Yoshimura, K. Imanaka-Yoshida, T. Yoshida, Y. Ikeda, T. Miyamoto, T. Ueno, K. Hamano, M. Hiroe, K. Aonuma, M. Matsuzaki, T. Imaizumi, and H. Aoki.
  • Journal Title: Scientific Reports Volume: 4 Issue: 1 Pages: 4051-4051
  • DOI: 10.1038/srep04051
  • Peer Reviewed / Open Access
• [Journal Article] Prostaglandin E2 Inhibits Elastogenesis in the Ductus Arteriosus via EP4 Signaling. (2014)
  • Author(s): Yokoyama U, Minamisawa S, Sh ioda A, Ishiwata R, Jin MH, Masuda M, Asou T, Sugimoto Y, Aoki II, Nakamura T, and Ishikawa Y
  • Journal Title: Circulation. Volume: 129 Issue: 4 Pages: 487-496
  • DOI: 10.1161/circulationaha.113.004726
  • Peer Reviewed / Open Access
• [Journal Article] 大動脈瘤の成因と分子病態 (2014)
  • Author(s): 青木浩樹
  • Journal Title: International Review of Thrombosis Volume: 9 Pages: 74-79
  • NAID: 40020138339
• [Presentation] Stat3 in vascular smooth muscle cells protects aorta from dissection by reinforcing aortic wall (2015)
  • Author(s): Saki Hirakata, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Aya Furusho, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Yoshihiro Fukumoto
  • Organizer: American Heart Association 2015 Scientific Sessions
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2015-11-12
  • Int'l Joint Research
• [Presentation] The Role of Macrophage STAT3 Signaling in Pathogenesis of Aortic Dissection (2015)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Yoshihiro Fukumoto
  • Organizer: American Heart Association 2015 Scientific Sessions
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2015-11-12
  • Int'l Joint Research
• [Presentation] Excessive NaCl Intake aggravates Aortic Dissection through IL- 17 Pathway (2015)
  • Author(s): Norifumi Nishida, Hiroki Aoki, Satoko Ohno, Michihide Nishihara, Aya Furusho, Saki Hirakata, Makiko Hayashi, Sohei Ito, Hideo Yasukawa, Yoshihiro Fukumoto
  • Organizer: American Heart Association 2015 Scientific Sessions
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2015-11-12
  • Int'l Joint Research
• [Presentation] Excessive sodium intake worsens aortic dissection via IL-17 pathway (2015)
  • Author(s): N. Nishida, H. Aoki, S. Ohno, M. Nishihara, A. Furusho, S. Hirakata, M. Hayashi, S. Ito, H. Yasukawa, Y. Fukumoto
  • Organizer: European Society for Cardiology Congress 2015
  • Place of Presentation: London, UK
  • Year and Date: 2015-08-29
  • Int'l Joint Research
• [Presentation] The role of macrophage STAT3 signaling in pathogenesis of aortic dissection (2015)
  • Author(s): S. Ohno, H. Aoki, M. Nishihara, A. Furusho, S. Hirakata, N. Nishida, S. Ito, M. Hayashi, H. Tanaka, Y. Fukumoto
  • Organizer: European Society for Cardiology Congress 2015
  • Place of Presentation: London, UK
  • Year and Date: 2015-08-29
  • Int'l Joint Research
• [Presentation] STAT3 in vascular smooth muscle cells protects aorta from dissection (2015)
  • Author(s): S. Hirakata, H. Aoki, M. Nishihara, S. Ohno, A. Furusho, N. Nishida, S. Ito, M. Hayashi, H. Tanaka, Y. Fukumoto
  • Organizer: European Society for Cardiology Congress 2015
  • Place of Presentation: London, UK
  • Year and Date: 2015-08-29
  • Int'l Joint Research
• [Presentation] Two faces of Janus (or STAT) in aortic dissection (2015)
  • Author(s): Hiroki Aoki
  • Organizer: 第47回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 仙台
  • Year and Date: 2015-07-09
  • Invited
• [Presentation] 大動脈解離における炎症応答 (2015)
  • Author(s): 青木浩樹
  • Organizer: 第15回日本抗加齢医学会総会
  • Place of Presentation: 福岡
  • Year and Date: 2015-05-29
  • Invited
• [Presentation] B cells and Immunoglobulin Promote the Development of Abdominal Aortic Aneurysm (2015)
  • Author(s): Aya Furusho, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Saki Hirakata, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Yoshihiro Fukumoto
  • Organizer: 第79回日本循環器学会
  • Place of Presentation: 大阪
  • Year and Date: 2015-04-24
• [Presentation] Excessive Sodium Intake Exacerbates Aortic Dissection through IL-17 Pathway (2015)
  • Author(s): Norifumi Nishida, Hiroki Aoki, Satoko Ohno, Michihide Nishihara, Aya Furusho, Saki Hirakata, Makiko Hayashi, Souhei Ito, Hideo Yasukawa, Yoshihiro Fukumoto
  • Organizer: 第79回日本循環器学会
  • Place of Presentation: 大阪
  • Year and Date: 2015-04-24
• [Presentation] Protective Role of STAT3 in Vascular Smooth Muscle Cells During the Development of Aortic Dissection (2015)
  • Author(s): Saki Hirakata, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Aya Furusho, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Yoshihiro Fukumoto
  • Organizer: 第79回日本循環器学会
  • Place of Presentation: 大阪
  • Year and Date: 2015-04-24
• [Presentation] Molecular Pathogenesis of Aortic Dissection: Macrophage-mediated Changes in Smooth Muscle-specific Gene Expression (2015)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Yoshihiro Fukumoto
  • Organizer: 第79回日本循環器学会
  • Place of Presentation: 大阪
  • Year and Date: 2015-04-24
• [Presentation] 塩分過剰摂取はIL-17経路を介して大動脈解離を増悪させる (2015)
  • 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、安川秀雄、福本義弘
  • Organizer: 第44回日本心脈管作動物質学会
  • Place of Presentation: 高松
  • Year and Date: 2015-02-06 – 2015-02-07
• [Presentation] Molecular pathogenesis of aortic dissection: The failure of protective mechanism of aortic walls (2014)
  • Author(s): Hiroki Aoki
  • Organizer: 第31回国際心臓研究学会（ISHR）日本部会
  • Place of Presentation: Nagoya, Japan
  • Year and Date: 2014-11-28 – 2014-11-29
  • Invited
• [Presentation] B cells Promote the Development of Abdominal Aortic Aneurysm through a proinflammatory response (2014)
  • Author(s): A Furusho, H Aoki, M Nishihara, S Ohno, S Hirakata, N Nishida, S Itou, Y Fukumoto
  • Organizer: 第31回国際心臓研究学会（ISHR）日本部会
  • Place of Presentation: Nagoya, Japan
  • Year and Date: 2014-11-27 – 2014-11-28
• [Presentation] Involvement of Macrophage IL-6 Signaling in Aortic Dissection (2014)
  • Author(s): S Ohno, H Aoki, M Nishihara, A Furusho, S Hirakata, N Nishida, S Itou, M Hayashi, Y Fukumoto
  • Organizer: 第31回国際心臓研究学会（ISHR）日本部会
  • Place of Presentation: Nagoya, Japan
  • Year and Date: 2014-11-27 – 2014-11-28
• [Presentation] Excessive Sodium Intake Exacerbates Acute Aortic Dissection through Proinflammatory IL-17 Pathway (2014)
  • Author(s): N Nishida, H Aoki, S Ohno, M Nishihara, A Furusho, S Hirakata, M Hayashi, S Itou, H Yasukawa, Y Fukumoto
  • Organizer: 第31回国際心臓研究学会（ISHR）日本部会
  • Place of Presentation: Nagoya, Japan
  • Year and Date: 2014-11-27 – 2014-11-28
• [Presentation] Protective Role of Stat3 in Vascular Smooth Muscle Cells During the Development of Acute Aortic Dissection (2014)
  • Author(s): S Hirakata, H Aoki, M Nishihara, S Ohno, A Furusho, N Nishida, S Itou, Y Fukumoto
  • Organizer: American Heart Association Scientific Sessions 2014
  • Place of Presentation: Chicago, IL, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] A Common Gene Network Governs The Cellular Phenotypes in Aortic Dissection (2014)
  • Author(s): S Ohno, H Aoki, M Nishihara, A Furusho, S Hirakata, N Nishida, S Itou, H Yasukawa, Y Fukumoto
  • Organizer: American Heart Association Scientific Sessions 2014
  • Place of Presentation: Chicago, IL, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Involvement of Macrophage Cytokine Signaling in Acute Aortic Dissection (2014)
  • Author(s): S Ohno, H Aoki, M Nishihara, A Furusho, S Hirakata, N Nishida, S Itou, H Yasukawa, Y Fukumoto
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] Involvement of B cells in Pathogenesis of Abdominal Aortic Aneurysm (2014)
  • Author(s): A Furusho, H Aoki, M Nishihara, S Ohno, S Hirakata, N Nishida, S Itou, Y Fukumoto
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] Tenascin C protects aorta from acute dissection in mice (2014)
  • Author(s): Aoki H, Kimura T, Yoshimura K, Shiraishi K, Imanaka-Yoshida K, Yoshida T, Ikeda Y, Miyamoto T, Ueno T, Fukumoto Y
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] Induction of Timp1 in Smooth Muscle Cells during Development of Abdominal Aortic Aneurysms (2014)
  • Author(s): Batmunkh B, Kokubo H, Kamata R, Fujii M, Aoki H, Ishida M, Ishita T, Yoshizumi M
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2014-04-14 – 2014-04-17