Molecular mechanism of aortic dissection : regulation of aortic wall tensile strength through cell-cell interactions

• Project/Area Number: 24390334
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• 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 山口大学大学院, 医学系研究科, 准教授(特命) (00322248) ; IMANAKA Kyoko 三重大学大学院, 医学系研究科, 准教授 (00242967) ; TANAKA Hiroyuki 久留米大学, 医学部, 教授 (70197466)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000); Fiscal Year 2014: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2012: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: 大動脈 / 細胞外マトリックス / 炎症 / 細胞間相互作用 / 循環器・高血圧 / 血管平滑筋細胞 / 組織強度 / 機械的ストレス

Outline of Final Research Achievements

Aortic dissection (AD) is a frequently fatal medical emergency for which molecular pathogenesis is largely unknown. We examined the role of JAK/STAT signaling in macrophages and vascular smooth muscle cells. In human AD tissue, macrophage infiltration was observed in adventitia and outer layer of the media. STAT3 was strongly activated in macrophages and outer layer of the medial smooth muscle cells. In mouse AD model, activation of JAK/STAT in macrophages promoted proinflammatory M1 differentiation and exacerbated AD progression. Activation of JAK/STAT in smooth muscle cells caused proliferation of adventitial fibroblast, deposition of collagen fibers and reinforcement of the tensile strength of aortic walls, thus preventing AD. In AD model, onset of AD was preceded by the activation of cell cycle, inflammatory response and suppression of smooth muscle cell-specific genes. Our findings indicate that JAK/STAT signaling is activated in AD and plays cell type-specific roles.

Research Products

• [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: 0 Pages: 74-79
  • NAID: 40020138339
• [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] Cardiomyocyte-specific transgenic expression of lysyl oxidase-like protein-1 induces cardiac hypertrophy in mice (2012)
  • Author(s): Ohmura, H.
  • Journal Title: Hypertens Res Volume: 35 Issue: 11 Pages: 1063-1068
  • DOI: 10.1038/hr.2012.92
  • Peer Reviewed
• [Journal Article] Macrophage-derived Angiopoietin- like Protein 2 Accelerates the Development of Abdominal Aortic Aneurysm. (2012)
  • Author(s): Tazume H, Miyata K, Tian Z, Endo M, Horiguchi H, Takahashi O, Horio E, Tsukano H, Kadomatsu T, Nakashima Y, Kunitomo R, Kaneko Y, Moriyama S, Sakaguchi H, Okamoto K, Hara M, Yoshinaga T, Yoshimura K, Aoki H, Araki K, Hao H, Kawasuji M, Oike Y.
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 32(6) Issue: 6 Pages: 1400-1409
  • DOI: 10.1161/atvbaha.112.247866
  • 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] 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] nvolvement of Macrophage IL-6 Signaling in Aortic Dissection (2014)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Yoshihiro Fukumoto
  • Organizer: 第31回国際心臓研究学会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-11-28 – 2014-11-29
• [Presentation] B cells Promote the Development of Abdominal Aortic Aneurysm through a Proinflammatory Response (2014)
  • Author(s): Aya Furusho, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Saki Hirakata, Norifumi Nishida, Yoshihiro Fukumoto
  • Organizer: 第31回国際心臓研究学会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-11-28 – 2014-11-29
• [Presentation] Protective role of STAT3 in vascular smooth muscle cells during the development of acute aortic dissection (2014)
  • Author(s): Saki Hirakata, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Aya Furusho, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Yoshihiro Fukumoto
  • Organizer: 第31回国際心臓研究学会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-11-28 – 2014-11-29
• [Presentation] Excessive Sodium Intake Exacerbates Acute Aortic Dissection through Proinflammatory IL-17 Pathway (2014)
  • Author(s): Norifumi Nishida, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Aya Furusho, Saki Hirakata, Sohei Ito, Makiko Hayashi, Hideo Yasukawa, Yoshihiro Fukumoto
  • Organizer: 第31回国際心臓研究学会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-11-28 – 2014-11-29
• [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
  • Place of Presentation: 名古屋
  • Year and Date: 2014-11-28 – 2014-11-29
  • Invited
• [Presentation] A Common Gene Network Governs The Cellular Phenotypes in Acute Aortic Dissection (2014)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Hideo Yasukawa, Yoshihiro Fukumoto
  • Organizer: American Heart Association Scientific sessions 2014
  • Place of Presentation: Chicago, IL, USA
  • Year and Date: 2014-11-16 – 2014-11-20
• [Presentation] Protective role of STAT3 in vascular smooth muscle cells during the development of acute aortic dissection (2014)
  • Author(s): Saki Hirakata, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Aya Furusho, Norifumi Nishida, Sohei Ito, Yoshihiro Fukumoto
  • Organizer: American Heart Association Scientific sessions 2014
  • Place of Presentation: Chicago, IL, USA
  • Year and Date: 2014-11-16 – 2014-11-20
• [Presentation] Molecular determinant of the development of acute aortic dissection (2014)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Yoshihiro Fukumoto
  • Organizer: ESC Congress 2014
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] The Role of B Cells in Pathogenesis of Abdominal Aortic Aneurysm (2014)
  • Author(s): Aya Furusho, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Saki Hirakata, Norifumi Nishida, Sohei Ito, Yoshihiro Fukumoto
  • Organizer: ESC Congress 2014
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] Involvement of Macrophage Cytokine Signaling in Acute Aortic Dissection (2014)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Yoshihiro Fukumoto
  • Organizer: he 18th International Vascular Biology Meeting
  • Place of Presentation: Kyoto
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] Involvement of B cells in Pathogenesis of Abdominal Aortic Aneurysm (2014)
  • Author(s): Aya Furusho, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Saki Hirakata, Norifumi Nishida, Sohei Ito, Yoshihiro Fukumoto
  • Organizer: he 18th International Vascular Biology Meeting
  • Place of Presentation: Kyoto
  • Year and Date: 2014-04-14 – 2014-04-17
• [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] B cell Promotes the Development of Abdominal Aortic Aneurysm (2014)
  • Author(s): Aya Furusho, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Saki Hirakata, Norifumi Nishida, Souhei Itou, Yoshihiro Fukumoto
  • 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, Souhei 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] 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] Involvement of B cells in Pathogenesis of Abdominal Aortic Aneurysm (2014)
  • Author(s): Aya Furusho, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Saki Hirakata, Norifumi Nishida, Souhei Itou, Yoshihiro Fukumoto
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: Kyoto
• [Presentation] Involvement of Macrophage Cytokine Signaling in Acute Aortic Dissection (2014)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Souhei Itou, Yoshihiro Fukumoto
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: Kyoto
• [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] Macrophage IL-6 Signaling is Critically Involved in the Progression of Acute Aortic Dissection (2013)
  • Author(s): Ohno S.
  • Organizer: 第77回日本循環器学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-16
• [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] 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 Scientific 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 Scientific 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
  • Invited
• [Presentation] Tenascin C protects aorta from acute dissection in mice (2012)
  • Author(s): Aoki H.
  • Organizer: American Society for Cell Biology 2012 Annual Meeting
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2012-12-17
• [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(高得点演題)
  • Year and Date: 2012-09-21
• [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
  • Year and Date: 2012-04-13
• [Presentation] Involvement of IL-6 1n Pathogenesis of Abdominal Aortic Aneurysm (2012)
  • Author(s): Nishihara M.
  • Organizer: 第77回日本循環器学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2012-03-16
• [Book] 新しい診断と治療のABC 大動脈瘤・大動脈解離 改訂第2版（分担執筆） (2013)
  • Author(s): 青木浩樹
  • Total Pages: 274
  • Publisher: 最新医学社
• [Remarks]
  • URL: http://www.kurume-shinzo.com