Macrophage differentiation in the pathogenesis of aortic dissection

• Project/Area Number: 15K10249
• 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: OHNO Satoko 久留米大学, 医学部, 助教 (80569418)
• Co-Investigator(Kenkyū-buntansha): 青木 浩樹 久留米大学, 付置研究所, 教授 (60322244) ; 田中 啓之 久留米大学, 医学部, 教授 (70197466)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 大動脈解離 / マクロファージ / 平滑筋 / サイトカイン / 増殖応答 / 炎症 / 機能分化 / 組織修復 / 炎症応答 / 細胞増殖

Outline of Final Research Achievements

We examined the hypothesis that macrophage Stat3 promotes the aortic dissection (AD) through the differentiation of macrophage and vascular smooth muscle cell (VSMC) . We found that macrophage-specific Socs3-KO (mSocs3-KO), in which Stat3 is enhanced specifically in macrophages, developed AD following minor aortic injury by aortic stress. In mSocs3-KO, macrophages predominantly differentiated to proinflammatory phenotype, resulting in the aortic inflammation enhancement. In the wild type, VSMC showed increase in tissue repair function upon aortic stress. In contrast, the tissue reparative phenotype of VSMC was suppressed in mSocs3-KO. As the mechanism of the dysregulation of VSMC, Ink4a/Arf, an inhibitor of proliferation which is also well known as the regulator of tissue repair, was highly expressed at minor injury in mSocs3-KO.
These results indicated that development of AD is driven by the imbalance of destruction and repair during the inflammation following the aortic stress.

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] 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] 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
• [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
• [Presentation] STAT3 Determines Differentiation of Macrophages and Progression of Aortic Dissection (2017)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Hidetoshi Akashi, Hiroyuki Tanaka, Yoshihiro Fukumoto
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢市教育プラザ此花体育館（石川県・金沢市）
  • Year and Date: 2017-03-17
• [Presentation] Central Role of mTOR Pathway in Molecular Pathogenesis of Aortic Dissection (2017)
  • Author(s): Makiko Hayashi, Hiroki Aoki, Satoko Ohno, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Yoshihiro Fukumoto
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢市教育プラザ此花体育館（石川県・金沢市）
  • 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, Satoko Ohno, Michihide Nishihara, Aya Furusho, Saki Hirakata, Sohei Ito, Makiko Hayashi, Yoshihiro Fukumoto
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢フォーラス（石川県・金沢市）
  • 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, Satoko Ohno, Michihide Nishihara, Saki Hirakata, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Hidetoshi Akashi, Hiroyuki Tanaka, Yoshihiro Fukumoto
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢市教育プラザ此花体育館（石川県・金沢市）
  • Year and Date: 2017-03-17
• [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, Yoshihiro Fukumoto
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: ヴィサージュ（石川県・金沢市）
  • Year and Date: 2017-03-17
• [Presentation] Myocardin-related transcription factor-A is required for development of aortic dissection (2017)
  • Author(s): Sohei Ito, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Aya Furusho, Saki Hirakata, Norifumi Nishida, Makiko Hayashi, 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: AHA2017
  • 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: AHA2017
  • 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] 大動脈解離の病態解明-mTOR経路を介する発症メカニズム- (2017)
  • Author(s): 林 真貴子、青木 浩樹、大野 聡子、西原 通秀、古荘 文、平方 佐季、西田 憲史、伊東 壮平、橋本 洋平、眞島 涼平、福本 義弘
  • Organizer: 第123回日本循環器学会九州地方会
• [Presentation] MRTF-Aは炎症応答、血管平滑筋細胞のアポトーシスを介して大動脈解離を引き起こす (2017)
  • Author(s): 伊東壮平、青木浩樹、西原通秀、大野聡子、古荘文、平方佐季、西田憲史、林真貴子、橋本洋平、眞島涼平、福本義弘
  • Organizer: 第123回日本循環器学会九州地方会
• [Presentation] Involvement of B Cell/Syk Axis in Development of Abdominal Aortic Aneurysm. (2017)
  • Author(s): 古荘 文、青木浩樹、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
• [Presentation] STAT3 in Smooth Muscle Cells Prevents Progression of Aortic Dissection by Reinforcing the Physical Strength of Aortic Walls (2017)
  • Author(s): Saki Hirakata, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Aya Furusho, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Yohei Hashimoto, Ryohei Majima, 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 if Extracellular Matrix (2017)
  • Author(s): Norifumi Nishida, Hiroki Aoki, Satoko Ohno, Michihide Nishihara, Aya Furusho, Saki Hirakata, Makiko Hayashi, Sohei Ito, Hideo Yasukawa, 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 Cells (2017)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Yoshihiro Fukumoto
  • 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 (2017)
  • Author(s): Sohei Ito, Hiroki Aoki, Satoko Ohno, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Makiko Hayashi, Yohei Hashimoto, Koichiro Kuwahara, Yoshihiro Fukumoto
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Macrophage Socs3 is the Determinant for the Development of Aortic Dissection (2016)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Hiroyuki Tanaka, Yoshihiro Fukumoto
  • Organizer: AHA 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): Sohei Ito, Hiroki Aoki, Michihide Nishihara, Satoko Ohno, Aya Furusho, Saki Hirakata, Norifumi Nishida, Makiko Hayashi, Yoshihiro Fukumoto
  • Organizer: AHA 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): 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
• [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, 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, 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 Causes Imbalance of Tissue Destruction and Protection to Promote Aortic Dissection (2016)
  • Author(s): Satoko Ohno, Hiroki Aoki, Michihide Nishihara, Aya Furusho, Saki Hirakata, Norifumi Nishida, Sohei Ito, Makiko Hayashi, Yoshihiro Fukumoto
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際会議場（宮城県 仙台市）
  • Year and Date: 2016-03-18
• [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: AHA 2015
  • Place of Presentation: Orlando ( USA )
  • Year and Date: 2015-11-07
  • 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: ESC congress 2015
  • Place of Presentation: London ( UK )
  • Year and Date: 2015-08-29
  • Int'l Joint Research
• [Presentation] Molecular Pathogenesis of Aortic Dissection: Macrophage-mediated Changes in Vascular 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回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府 大阪市）
  • Year and Date: 2015-04-24
• [Book] Mouse Models of Vascular Diseases (2016)
  • Author(s): Hiroki Aoki, Satoko Ohno, Aya Furusho, Michihide Nishihara, Norifumi Nishida, Saki Hirakata, Koichi Yoshimura
  • Total Pages: 296
  • Publisher: Springer Japan