Novel therapeutic strategy for aortic aneurysm targeting master cytokine and cellular senescence

• Project/Area Number: 21390367
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General 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 (00322248) ; YASUKAWA Hideo 久留米大学, 医学部, 准教授 (60289361)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2011: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2010: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2009: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 循環器・高血圧 / 細胞・組織 / シグナル伝達 / トランスレーショナルリサーチ / 外科

Research Abstract

Abdominal aortic aneurysm(AAA) is common to eldery people, of which molecula pathogenesis is largely unknown. We hypothesized that IL-6 may be the master cytokine for regulating the chronic inflammation and tissue destruction in AAA. Indeed, IL-6 was one of the most abundantly expressed cytokines and regulating a subset of proinflammatory cytokines, including VEGF and MCP-3, in human AAA tissue. In mouse model of AAA, IL-6 expression was associated with the expansion of aortic diameter, and was involved in the progression of AAA. Although macrophages are important in pathogenesis of AAA, enhanced IL-6 signaling in macrophages did not affect AAA development. Thus, IL-6-dependent development of AAA appeared to be mediated by cell types other than macrophages. Unexpectedly, we discovered that macrophage IL-6 signaling was critically involved in the development of acute aortic dissection. In the future studies, we will address which cell type is responsible for the IL-6-dependent devopment of AAA, and how macrophage IL-6 is involved in the pathogenesis of aortic dissection.

Research Products

• [Journal Article] Inhibition of EP4 Signaling Attenuates Aortic Aneurysm Formation (2012)
  • Author(s): Yokoyama, U., Aoki, H., et al
  • Journal Title: PLoS ONE
  • Peer Reviewed
• [Journal Article] Macrophage-derived Angiopoietin-like Protein 2 Accelerates Development of Abdominal (2012)
  • Author(s): Tazume, H., Aoki, H., et al
  • Journal Title: Aortic Aneurysm Arterioscler Thromb Vasc Biol Volume: (in press)
  • Peer Reviewed
• [Journal Article] Cardiomyocyte-specific transgenic expression of lysyl oxidase-like protein-1 induces cardiac hypertrophy in mice (2012)
  • Author(s): Ohmura, H. Aoki, H., et al
  • Journal Title: Hypertens Res Volume: (in press)
  • Peer Reviewed
• [Journal Article] Inhibition of eNOS phosphorylation mediates endothelial dysfunction in renal failure : new effect of asymmetric dimethylarginine (2012)
  • Author(s): Kajimoto, H., Yasukawa, H., Aoki, H., et al
  • Journal Title: Kidney Int Volume: 81 Pages: 762-768
  • Peer Reviewed
• [Journal Article] Innocent bystander? Intraluminal thrombus in abdominal aortic aneurysm (2011)
  • Author(s): Yoshimura, K., Ikeda, Y. & Aoki, H
  • Journal Title: Atherosclerosis Volume: 218 Pages: 285-286
  • Peer Reviewed
• [Journal Article] Deletion of EP4 on bone marrow-derived cells enhances inflammation and angiotensin II-induced abdominal aortic aneurysm formation (2011)
  • Author(s): Tang, E. H., Aoki, H., et al
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 31 Pages: 261-269
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor promotes an anti-inflammatory cytokine profile in human abdominal aortic aneurysm tissue (2011)
  • Author(s): Shintani, Y., Aoki, H., et al
  • Journal Title: Atherosclerosis Volume: 216 Pages: 307-312
  • Peer Reviewed
• [Journal Article] Tenascin-C is expressed in abdominal aortic aneurysm tissue with an active degradation process (2011)
  • Author(s): Kimura, T., Aoki, H., Yoshimura, K., et al
  • Journal Title: Pathol Int Volume: 61 Pages: 559-564
  • NAID: 10030721173
  • Peer Reviewed
• [Journal Article] Role of vascular endothelial growth factor-A in development of abdominal aortic aneurysm (2011)
  • Author(s): Kaneko, H., Aoki, H., Yoshimura, K., et al
  • Journal Title: Cardiovasc Res Volume: 91 Pages: 358-367
  • Peer Reviewed
• [Journal Article] Resveratrol prevents the development of abdominal aortic aneurysm through attenuation of inflammation, oxidative stress, and neovascularization (2011)
  • Author(s): Kaneko, H., Aoki, H., Yoshimura, K., et al
  • Journal Title: Atherosclerosis Volume: 217 Pages: 350-357
  • Peer Reviewed
• [Journal Article] Tenascin-C is expressed in abdominal aortic aneurysm tissue with an active degradation process (2011)
  • Author(s): Taizo Kimura
  • Journal Title: Pathol Int Volume: 61 Issue: 10 Pages: 559-564
  • DOI: 10.1111/j.1440-1827.2011.02699.x
  • Peer Reviewed
• [Journal Article] 慢性炎症と大動脈瘤 (2011)
  • Author(s): 青木浩樹, 吉村耕一
  • Journal Title: 呼吸と循環 Volume: 59 Pages: 883-889
• [Journal Article] 特集「慢性炎症と生活習慣病・癌」大動脈瘤-慢性炎症のモデル疾患 (2011)
  • Author(s): 青木浩樹, 吉村耕一
  • Journal Title: 医学のあゆみ Volume: 236 Pages: 271-277
• [Journal Article] 大動脈瘤とテネイシンC (2011)
  • Author(s): 吉村耕一, 木村泰三, 青木浩樹
  • Journal Title: 呼吸と循環 Volume: 59 Pages: 1107-1113
• [Journal Article] Hepatocyte growth factor promotes an anti-inflammatory cytokine profile in human abdominal aortic aneurysm tissue (2011)
  • Author(s): Shintani, Y., Nishihara, M., Ohno, S., Furusho, A., Aoki, H., Hiromatsu, S.-i, Akashi, H., Imaizumi, T., Aoyagi, S.
  • Journal Title: Atherosclerosis Volume: in press(in press)
  • Peer Reviewed
• [Journal Article] 大動脈瘤-慢性炎症のモデル疾患 (2011)
  • Author(s): 青木浩樹, 吉村耕一
  • Journal Title: 医学のあゆみ 特集「慢性炎症と生活習慣病・癌」 Volume: 236 Pages: 271-277
• [Journal Article] Isoform-Specific Roles of Protein Phosphatase 1 Catalytic Subunits in Sarcoplasmic Reticulum-Mediated Ca2+Cycling (2010)
  • Author(s): Aoyama, H., Aoki, H., Yoshimura, K., et al
  • Journal Title: Cardiovasc Res Volume: 89 Pages: 79-88
  • Peer Reviewed
• [Journal Article] Isoform-Specific Roles of Protein Phosphatase 1 Catalytic Subunits in Sarcoplasmic Reticulum-Mediated Ca2+ Cycling (2010)
  • Author(s): Aoyama, H., Ikeda, Y., Miyazaki, Y., Yoshimura, K., Nishino, S., Yamamoto, T., Yano, M., Inui, M., Aoki, H., Matsuzaki, M.
  • Journal Title: Cardiovasc Res Volume: 89 Pages: 79-88
  • Peer Reviewed
• [Journal Article] Helicobacter pylori CagA inhibits endocytosis of cytotoxin VacA in host cells (2010)
  • Author(s): Akada, J.K., Aoki, H., Torigoe, Y., Kitagawa, T., Kurazono, H., Hoshida, H., Nishikawa, J., Terai, S., Matsuzaki, M., Hirayama, T., Nakazawa, T., Akada, R., Nakamura, K.
  • Journal Title: Dis Model Mech Volume: 3 Pages: 605-617
  • Peer Reviewed
• [Journal Article] 大動脈瘤の分子細胞生物学:最近の進歩 (2010)
  • Author(s): 青木浩樹
  • Journal Title: Heart View Volume: 14 Pages: 53-57
  • Peer Reviewed
• [Journal Article] 大動脈瘤と慢性炎症 (2010)
  • Author(s): 青木浩樹
  • Journal Title: 細胞 特集「生活習慣病と慢性炎症」 Volume: 42 Pages: 464-467
• [Journal Article] JNK活性化と大動脈疾患 (2010)
  • Author(s): 吉村耕一, 青木浩樹, 濱野公一, 松崎益徳
  • Journal Title: 日本内科学会雑誌特集「大動脈疾患-大動脈解離と胸腹部大動脈瘤:診断と治療の進歩」 Volume: 99 Pages: 237-244
  • NAID: 10026330366
• [Journal Article] 再充填可能な薬剤徐放性ステントグラフトが大動脈瘤治療を変える (2010)
  • Author(s): 吉村耕一, 青木浩樹
  • Journal Title: Mebio Volume: 28 Pages: 132-141
• [Journal Article] Lysyl oxidase resolves inflammation by reducing monocyte chemoattractantprotein-1 in abdominal aortic aneurysm (2009)
  • Author(s): Onoda M, Yoshimura K, Aoki H, Ikeda Y, Morikage N, et al.
  • Journal Title: Atherosclerosis 208 Pages: 366-369
  • Peer Reviewed
• [Journal Article] RhoH plays critical roles in Fc epsilon RI-dependent signal transduction in mast cells (2009)
  • Author(s): Oda H, Fujimoto M, Patrick MS, Aoki H, et al.
  • Journal Title: J Immunol 182 Pages: 957-962
  • Peer Reviewed
• [Journal Article] 特集「大動脈瘤の分子細胞生物学」(企画担当) (2009)
  • Author(s): 青木浩樹
  • Journal Title: 血管医学 10 Pages: 7-71
• [Journal Article] 臨床と基礎の接点 (2009)
  • Author(s): 吉村耕一, 青木浩樹, 小櫃由樹生, 重松宏, 松崎益徳
  • Journal Title: 血管医学 10 Pages: 13-19
• [Journal Article] Inhibition of EP4 Signaling Attenuates Aortic Aneurysm Formation
  • Author(s): U.Yokoyama, et al
  • Journal Title: PLoS ONE Volume: (in press)
  • Peer Reviewed
• [Journal Article] Macrophage-derived Angiopoietin-like Protein 2 Accelerates Development of Abdominal Aortic Aneurysm
  • Author(s): H.Tazume, et al
  • Journal Title: Arterioscler Thromb Vase Biol Volume: (in press)
  • Peer Reviewed
• [Journal Article] Cardiomyocyte-specific transgenic expression of lysyl oxidase-like protein-1 induces cardiac hypertrophy in mice
  • Author(s): H.Ohmura, et al
  • Journal Title: Hypertens Res Volume: (in press)
  • Peer Reviewed
• [Journal Article] Role of vascular endothelial growth factor-A in development of abdominal aortic aneurysm
  • Author(s): Kaneko, H., Anzai, T., Takahashi, T., Kohno, T., Shimoda, M., Sasaki, A., Shimizu, H., Nagai, T., Maekawa, Y., Yoshimura, K., Aoki, H., Yoshikawa, T., Okada, Y., Yozu, R., Ogawa, S., Fukuda, K.
  • Journal Title: Cardiovasc Res Volume: in press(in press)
  • Peer Reviewed
• [Presentation] Macrophage IL-6 signaling is critically involved in the pathogenesis of acute aortic dissection (2012)
  • Author(s): Ohno S, et al
  • Organizer: 第76回日本循環器学会総会・学術集会
  • Place of Presentation: 福岡
• [Presentation] Invited Keynote lecture : Inflammatory Response in Aortic Diseases (2012)
  • Author(s): Aoki H
  • Organizer: 第76回日本循環器学会総会・学術集会
  • Place of Presentation: 福岡
• [Presentation] JAK/STAT pathway is highly active and regulates a subset of chemokines in human abdominal aortic aneurysm (2011)
  • Author(s): Ohno S, Aoki H, et al
  • Organizer: 第75回日本循環器学会総会・学術集会
  • Place of Presentation: 横浜
• [Presentation] Activation of hypoxia inducible factor-erythropoietin pathway may prevent acute myocardial injury during remote ischemic preconditioning (2011)
  • Author(s): Oba T, Yasukawa H, Aoki H, et al
  • Organizer: American Heart Association Scientific Settions 2011
  • Place of Presentation: Orlando, FL, USA
• [Presentation] Inhibition of camkii-and erk-mediated enos phosphorylation impairs endothelial function in renal failure mice : New effect of asymmetric dimethylarginine (2011)
  • Author(s): Kajimoto H, Aoki H, et al
  • Organizer: American Heart Association Scientific Settions 2011
  • Place of Presentation: Orlando, FL, USA
• [Presentation] Development of a Novel Hybrid Device with Rechargeable Drug-Eluting Capability for Minimally Invasive Treatment of Aortic Aneurysms (2011)
  • Author(s): Yoshimura K, Aoki H, et al
  • Organizer: American Heart Association Scientific Settions 2011
  • Place of Presentation: Orlando, FL, USA
• [Presentation] Inhibition of camkii- and erk-mediated enos phosphorylation impairs endothelial function in renal failure mice : New effect of asymmetric dimethylarginine (2011)
  • Author(s): Kajimoto H, et al
  • Organizer: American Heart Association Scientific Settions 2011
  • Place of Presentation: Orlando, FL, USA
• [Presentation] Molecular network for the homeostasis of aortic tissue (2010)
  • Author(s): Hiroki Aoki, Taizo Kimura, Koichi Yoshimura, Kyoko Imanaka-Yoshida, Toshimichi Yoshida, Kazutaka Aonuma, Michiaki Hiroe, Tsutomu Imaizumi, Masunor Matsuzaki
  • Organizer: 第18回日本血管生物医学会
  • Place of Presentation: 大阪
  • Year and Date: 2010-12-03
• [Presentation] Pinpoint Drug Delivery to Any Lesion in the Body : A Novel Hybrid Device with Rechargeable Drug-Eluting Capability for Personalized and Minimally Invasive Treatment of Aortic Aneurysms (2010)
  • Author(s): Koichi Yoshimura, Hiroki Aoki
  • Organizer: Technology Showcase of Hiroshima University and Western Japan's Innovative Academia, JETRO East
  • Place of Presentation: ew York City, NY, USA
  • Year and Date: 2010-06-06
• [Presentation] JAK/STAT系による大動脈瘤のサイトカインネットワーク制御 (2010)
  • Author(s): 大野聡子、青木浩樹、西原通秀、今泉勉
  • Organizer: 第33回日本高血圧学会
  • Place of Presentation: 福岡
• [Presentation] ヒト大動脈瘤組織におけるマトリクス・メタロプロテアーゼ系の発現パターン解析 (2010)
  • Author(s): 西原通秀、青木浩樹、大野聡子、今泉勉
  • Organizer: 第33回日本高血圧学会
  • Place of Presentation: 福岡
• [Presentation] Tenascin-C Is a Molecular Shock-Absorber That Protects Aorta from Dissection (2010)
  • Author(s): H. Aoki, T. Kimura, K. Yoshimura, K. Imanaka-Yoshida, T. Yoshida, K. Aonuma, M. Hiroe, T. Imaizumi, M. Matsuzaki
  • Organizer: American Society for Cell Biology Annual Meeting 2010
  • Place of Presentation: Philadelphia, PA, USA
• [Presentation] Prostaglandin EP4 Signaling Negatively Regulates Vascular Elastic Fiber Assembly in the Ductus Arteriosus (2010)
  • Author(s): Utako Yokoyama, Aki Shioda, Yuko Kato, Toshihide Asou, Hiroki Aoki, Tomoyuki Nakamura, Susumu Minamisawa, and Yoshihiro Ishikawa
  • Organizer: American Heart Association Scientific Sessions 2010
  • Place of Presentation: Chicago, IL, USA
• [Presentation] Tenascin-C Protects Aortic Tissue from The Development of Aortic Dissection, Cell Symposia (2010)
  • Author(s): Taizo Kimura, Koichi Yoshimura, Hiroki Aoki, Kyoko Imanaka-Yoshida, Toshimichi Yoshida, Kazutaka Aonuma Michiaki Hiroe, Tsutomu Imaizumi, Masunori Matsuzaki
  • Organizer: Cell Inflammation and Disease Symposium
  • Place of Presentation: Lisbon, Portugal
• [Presentation] Tenascin-C Protects Aortic Tissue From Multiple Insults Against The Development of Aortic Aneurysm (2010)
  • Author(s): Kimura T, Yoshimura K, Aoki H, Ikeda Y, Imanaka-Yoshida K, Hiroe M, Imaizumi T, Aonuma K and Matsuzaki M
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
• [Presentation] A Novel Hybrid Device for Personalized and Minimally Invasive Treatment of Aortic Aneurysms (2010)
  • Author(s): Yoshimura K, Aoki H, Ikeda Y, Matsuzaki M, Hamano K
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
• [Presentation] シンポジウム「大動脈疾患治療UP to DATE」Molecular Network of Abdominal Aortic Aneurysm (2010)
  • Author(s): Aoki H, Yoshimura K, Kimura T, Imanaka-Yoshida K, Aonuma K, Hiroe M, Shigematsu H, Matsuzaki M and Imaizumi T
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
• [Presentation] Tenascin-C Protects Aortic Tissue from The Development of Aortic Dissection (2010)
  • Author(s): Taizo Kimura, Koichi Yoshimura, Hiroki Aoki, Kyoko Imanaka-Yoshida, Toshimichi Yoshida, Kazutaka Aonuma, Michiaki Hiroe, Tsutomu Imaizumi, Masunori Matsuzaki
  • Organizer: Cell Symposia : Cell Inflammation and Disease Symposium
  • Place of Presentation: Lisbon, Portugal
• [Presentation] ヒト大動脈瘤組織におけるマトリクス・メタロブロテアーゼ系の発現パターン解析 (2010)
  • Author(s): 西原通秀、青木浩樹、大野聡子、今泉勉
  • Organizer: 第33回日本高血圧学会
  • Place of Presentation: 福岡
• [Presentation] シンポジウム「大動脈疾患治療 UP to DATE」Molecular Network of Abdominal Aortic Aneurysm (2010)
  • Author(s): 青木浩樹, 吉村耕一, 木村泰三, 今中-吉田恭子, 青沼和隆, 廣江道昭, 重松宏, 松崎益徳, 今泉勉
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
• [Presentation] ワークショップ「慢性炎症:生活習慣病・癌に共通する基盤病態」炎症のタイムカプセル:大動脈瘤をモデル疾患とした慢性炎症の病態解明 (2009)
  • Author(s): 青木浩樹, 吉村耕一, 木村泰三, 宮本貴宣, 今中-吉田恭子, 吉田利通, 浜本義彦, 青沼和隆, 廣江道昭, 重松宏, 松崎益徳, 今泉勉
  • Organizer: 第32回日本分子生物学会
  • Place of Presentation: 横浜
• [Presentation] Symposium "Recent advances in pathobiology and treatment of aortic aneurysms" Molecular Pathogenesis of Abdominal Aortic Aneurysm (2009)
  • Author(s): H. Aoki, K. Yoshimura, H. Shigematsu, T. Imaizumi, M. Matsuzaki
  • Organizer: 第41回日本動脈硬化学会
  • Place of Presentation: 下関
• [Presentation] Critical role of JNK2 for development of abdominal aortic aneurysm in a murine model (2009)
  • Author(s): Koichi Yoshimura, Hiroki Aoki, Akira Furutani, Masunori Matsuzaki and Kimikazu Hamano
  • Organizer: Asian Society for Vascular Surgery Annual Congress 2009
  • Place of Presentation: Busan, Korea
• [Presentation] Tenascin-C Has A Protective Role during The Development of Aortic Aneurysm (2009)
  • Author(s): Kimura T, Yoshimura K, Aoki H, Ikeda Y, Hamano K, Imanaka-Yoshida K, Yoshida T, Hiroe M, Aonuma K and Matsuzaki M
  • Organizer: American Heart Association Scientific Sessions 2009
  • Place of Presentation: Orlando, FL, USA
• [Presentation] Tenascin C Protects Aortic Tissue From Multiple Insults Against The Development of Aortic Aneurysm (2009)
  • Author(s): Kimura T, Yoshimura K, Aoki H, Imanaka-Yoshida K, Yoshida T, Aonuma K, Hiroe M, Imaizumi T and Matsuzaki M
  • Organizer: American Society for Cell Biology Annual Meeting 2009
  • Place of Presentation: San Diego, CA, USA
• [Presentation] A Novel Hybrid Device with Rechargeable Drug-Eluting Capability for Personalized and Minimally Invasive Treatment of Aortic Aneurysms, Technology Showcase of Hiroshima University and Western Japan's Innovative Academia
  • Author(s): Koichi Yoshimura and Hiroki Aoki
  • Organizer: JETRO East
  • Place of Presentation: New York City, NY, USA
• [Book] モデル動物利用マニュアル「循環器疾患」(編北徹et al.) (2010)
  • Author(s): 吉村耕一, 青木浩樹
  • Publisher: エル・アイ・シー
• [Book] 循環器疾患のサイエンス(小室一成編)分担執筆『大動脈瘤研究の現状と課題』 (2010)
  • Author(s): 青木浩樹, 吉村耕一
  • Publisher: 南山堂
• [Book] 新・心臓病診療プラクティス15 血管疾患を診る・治す(小室一成編)分担執筆『大動脈瘤:薬物治療は進行を止めるか?』 (2010)
  • Author(s): 青木浩樹
  • Publisher: 文光堂
• [Book] モデル動物利用マニュアル「循環器疾患」(北徹,堀内久徳,柳田素子,猪原匡史,冨本秀和,並河徹編)分担執筆『大動脈瘤モデル』 (2010)
  • Author(s): 吉村耕一, 青木浩樹
  • Publisher: エル・アイ・シー
• [Book] 大動脈瘤研究の現状と課題.『循環器疾患のサイエンス』 (2010)
  • Author(s): 青木浩樹, 吉村耕一
  • Total Pages: 236
  • Publisher: 南山堂
• [Remarks]
  • URL: http://www.kurume-shinzo.com/
• [Remarks]
  • URL: http://www.med.kurume-u.ac.jp/med/kucri/index.html
• [Patent(Industrial Property Rights)] 動脈瘤予防および/または治療剤 (2011)
  • Inventor(s): 吉村耕一、青木浩樹、松崎益徳
  • Industrial Property Rights Holder: 山口大学
  • Acquisition Date: 2011-02-25