The role of developmental program in pathogenesis of acute aortic dissection

• Project/Area Number: 24659640
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Thoracic 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): YOSHIMURA Koichi 山口大学, 医学系研究科, 准教授(特命) (00322248) ; IMANAKA Kyoko (YOSHIDA Kyoko) 三重大学, 医学系研究科, 准教授 (00242967)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 心臓大血管外科学 / 大動脈解離 / 器官形成 / 大動脈 / 発生学 / 血管平滑筋 / メカノストレス

Research Abstract

The goals of this project were 1) to clarify the role of developmental gene program in the protection of aortic walls against the hemodynamic and humoral stress, and 2) to establish the mouse model of acute aortic dissection. We identified tenascin C as a stress-activated molecular safeguard to reinforce the aortic walls, of which failure leads to the development of acute aortic dissection. We found that the expression pattern of tenascin C does not match with the distribution of the cell lineages during the development of the aorta in mouse embryos, suggesting that heterogeneity in the tenascin C expression pattern is determined by the distribution of aortic stress rather than the endogenous developmental gene program. As a second goal of this project, we established a mouse model of acute aortic dissection that recapitulates the phenotype of human disease by continuous infusion of beta-aminopropionitrile and angiotensin II.

Research Products

• [Journal Article] Prostaglandin E2 Inhibits Elastogenesis in the Ductus Arteriosus via EP4 Signaling (2014)
  • Author(s): Yokoyama, U., S. Minamisawa, A. Shioda, R. Ishiwata, M.H. Jin, M. Masuda, T. Asou, Y. Sugimoto, H. Aoki, T. Nakamura, and Y. Ishikawa
  • Journal Title: Circulation Volume: 129 Pages: 487-496
  • 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: Sci Rep Volume: 4 Pages: 4051-4051
  • 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] Recent advances in pharmacotherapy development for abdominal aortic aneurysm (2012)
  • Author(s): Yoshimura, K., and H. Aoki
  • Journal Title: Int J Vasc Med Volume: 2012 Pages: 648167-648167
  • Peer Reviewed
• [Journal Article] Inhibition of EP4 signaling attenuates aortic aneurysm formation (2012)
  • Author(s): Yokoyama, U., R. Ishiwata, M.H. Jin, Y. Kato, O. Suzuki, H. Jin, Y. Ichikawa, S. Kumagaya, Y. Katayama, T. Fujita, S. Okumura, M. Sato, Y. Sugimoto, H. Aoki, S. Suzuki, M. Masuda, S. Minamisawa, and Y. Ishikawa
  • Journal Title: PLoS One Volume: 7
  • Peer Reviewed
• [Journal Article] Macrophage-derived angiopoietin-like protein 2 accelerates development of abdominal aortic aneurysm (2012)
  • Author(s): Tazume, H., K. Miyata, Z. Tian, M. Endo, H. Horiguchi, O. Takahashi, E. Horio, H. Tsukano, T. Kadomatsu, Y. Nakashima, R. Kunitomo, Y. Kaneko, S. Moriyama, H. Sakaguchi, K. Okamoto, M. Hara, T. Yoshinaga, K. Yoshimura, H. Aoki, K. Araki, H. Hao, M. Kawasuji, and Y. Oike
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 32 Pages: 1400-1409
  • Peer Reviewed
• [Journal Article] Cardiomyocyte-specific transgenic expression of lysyl oxidase-like protein-1 induces cardiac hypertrophy in mice (2012)
  • Author(s): Ohmura, H., H. Yasukawa, T. Minami, Y. Sugi, T. Oba, T. Nagata, S. Kyogoku, H. Ohshima, H. Aoki, and T. Imaizumi
  • Journal Title: Hypertens Res Volume: 35 Pages: 1063-1068
  • Peer Reviewed
• [Journal Article] Inhibition of eNOS Phosphorylation Mediates Endothelial Dysfunction in Renal Failure : New Effect of Asymmetric Dimethylarginine (2012)
  • Author(s): Kajimoto H, Kai H, Imaizumi T(他6人9番目)
  • Journal Title: Kidney International Volume: 81 Issue: 8 Pages: 762-768
  • DOI: 10.1038/ki.2011.476
  • Peer Reviewed
• [Journal Article] Heart Failure-inducible gene therapy targeting protein phosphatase 1 prevents progressive left ventricular remodeling (2012)
  • Author(s): Yosuke Miyazaki
  • Journal Title: PLOS ONE Volume: 7 Issue: 4 Pages: 35875-35875
  • DOI: 10.1371/journal.pone.0035875
  • Peer Reviewed
• [Journal Article] Inhibition of EP4 signaling attelluates aortic aneurysm formation (2012)
  • Author(s): Yokoyama U
  • Journal Title: PLoS One Volume: 7 Issue: 5 Pages: e36724-e36724
  • DOI: 10.1371/journal.pone.0036724
  • Peer Reviewed
• [Journal Article] 大動脈瘤の分子機序 (2012)
  • Author(s): 青木浩樹
  • Journal Title: Heart View Volume: 16 Pages: 46-51
• [Presentation] Hemodynamic stress on aortic walls : adaptation and maladaptation (2014)
  • Author(s): Hiroki Aoki
  • Organizer: 第91回日本生理学会大会
  • Place of Presentation: 鹿児島
• [Presentation] 大動脈疾患における炎症と組織リモデリング (2014)
  • Author(s): 青木浩樹
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京
• [Presentation] Macrophage Cytokine Signaling Determines the Development of Acute Aortic Dissection (2014)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Tsutomu Imaizumi, Yoshihiro Fukumoto
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京
• [Presentation] B cell Promotes the Development of Abdominal Aortic Aneurysm (2014)
  • Author(s): Aya Furusho, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Norifumi Nishida, Saki Hirakata, Sohei Ito, Hideo Yasukawa, Yoshihiro Fukumoto
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京
• [Presentation] Hemodynamic stress on aortic walls: adaptation and maladaptation (2014)
  • Author(s): Hiroki Aoki
  • Organizer: 第91回日本生理学会大会
  • Place of Presentation: 鹿児島
  • Invited
• [Presentation] 大動脈疾患における炎症と組織リモデリング (2014)
  • Author(s): Hiroki Aoki
  • Organizer: 第78回 日本循環器学会学術集会
  • Place of Presentation: 東京
  • Invited
• [Presentation] Tenascin C protects aorta from acute dissection in mice (2014)
  • Author(s): Hiroki Aoki, Taizo Kimura, Koichi Yoshimura, Kozoh Shiraishi, Kyoko Imanaka-Yoshida, Toshimichi Yoshida, Yasuhiro Ikeda, Takanobu Miyamoto, Takafumi Ueno, Yoshihiro Fukumoto
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: Kyoto
• [Presentation] Deciphering the Sequential Molecular Events during Onset of Acute Aortic Dissection (2013)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Souhei Itou, Tsutomu Imaizumi
  • Organizer: American Heart Association Sientific Sessions 2013
  • Place of Presentation: Dallas, TX, USA
• [Presentation] Involvement of IL-6 in Pathogenesis of Abdominal Aortic Aneurysm (2013)
  • Author(s): Michihide Nishihara, Hiroki Aoki, Satoko Ohno, Aya Furusho, Saki Hirakata, Norifumi Nishida, Shohei Ito, Hideo Yasukawa, and Tsutomu Imaizumi
  • Organizer: American Heart Association Sientific Sessions 2013
  • Place of Presentation: Dallas, TX, USA
• [Presentation] 大動脈疾患におけるdanger signalと炎症 (2013)
  • Author(s): 青木浩樹
  • Organizer: 第21回日本血管生物医学会学術集会
  • Place of Presentation: 大阪
• [Presentation] Tenascin-C in cardiovascular tissue injury and repair (2013)
  • Author(s): Imanaka-Yoshida, Naoshi Shimojo, Hiroki Aoki, Koichi Yoshimura, Toshimichi Yoshida
  • Organizer: FASEB Summer Meeting"MATRICELLULAR PROTEINS IN DEVELOPMENT, HEALTH, AND DISEASE"
  • Place of Presentation: Vermont Academy, Saxtons River, VT Kyoko
• [Presentation] Involvement of IL-6 in Pathogenesis of Abdominal Aortic Aneurysm (2013)
  • Author(s): Michihide Nishihara, Hiroki Aoki, Satoko Ohno, Aya Furusho, Saki Hirakata, Norifumi Nishida, Shohei Ito, Hideo Yasukawa, and Tsutomu Imaizumi
  • Organizer: 第77回日本循環器学会学術集会
  • Place of Presentation: 横浜
• [Presentation] Macrophage IL-6 Signaling is Critically Involved in the Progression of Acute Aortic Dissection (2013)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Souhei Itou, Tsutomu Imaizumi
  • Organizer: 第77回日本循環器学会学術集会
  • Place of Presentation: 横浜
• [Presentation] Tenascin-C in cardiovascular tissue injury and repair (2013)
  • Author(s): Kyoko Imanaka-Yoshida, Naoshi Shimojo, Hiroki Aoki, Koichi Yoshimura, Toshimichi Yoshida
  • Organizer: 2013 FASEB Summer Meeting “MATRICELLULAR PROTEINS IN DEVELOPMENT, HEALTH, AND DISEASE”
  • Place of Presentation: Vermont Academy, Saxtons River, VT, USA
• [Presentation] 大動脈疾患における danger signal と炎症 (2013)
  • Author(s): 青木浩樹
  • Organizer: 第21回日本血管生物医学会学術集会
  • Place of Presentation: 大阪
  • Invited
• [Presentation] Tenascin C protects aorta from acute dissection in mice (2012)
  • Author(s): Aoki H, Kimura T, Yoshimura K, Shiraishi K, Imanaka-Yoshida K, Yoshida T, Ikeda Y, Miyamoto T, Ueno T, Hamano K, Hiroe M, Aonuma K Matsuzaki M, Imaizumi T
  • Organizer: American Society for Cell Biology 2012 Annual Meeting
  • Place of Presentation: San Francisco, CA, USA
• [Presentation] Macrophage IL-6 Signaling is Critically Involved in the Pathogenesis of Acute Aortic Dissection (2012)
  • Author(s): Ohno S, Aoki H, Nishihara M, Furusho A, Hirakata S, Nishida N, Yasukawa H, and Imaizumi T
  • Organizer: 第35回日本高血圧学会総会
  • Place of Presentation: 名古屋(高得点演題)
• [Presentation] 大動脈瘤と大動脈解離におけるSTAT3経路の役割 (2012)
  • Author(s): 大野聡子
  • Organizer: 第49回日本臨床分子医学会学術集会
  • Place of Presentation: 京都
• [Presentation] Macrophage IL-6 Signaling is Critically Involved in the Pathogenesis of Acute Aortic Dissection (2012)
  • Author(s): Ohno S.
  • Organizer: 第35回日本高血圧学会総会
  • Place of Presentation: 名古屋
• [Remarks] 久留米大学医学部心臓・血管内科
  • URL: http://www.kurume-shinzo.com
• [Patent(Industrial Property Rights)] 薬物送達システム (2014)
  • Inventor(s): 青木浩樹、吉村耕一、他4名
  • Industrial Property Rights Holder: 山口大学
  • Industrial Property Rights Type: 特許
  • Acquisition Date: 2014-02-14