Dysregulation of tissue homeostasis by cellular senescence in pathogenesis of aortic dissection

• Project/Area Number: 19H03743
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 55030:Cardiovascular surgery-related
• Research Institution: Kurume University
• Principal Investigator: Aoki Hiroki 久留米大学, 付置研究所, 教授 (60322244)
• Co-Investigator(Kenkyū-buntansha): 田中 啓之 久留米大学, 医学部, 教授 (70197466)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2021: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2020: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2019: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 大動脈解離 / 細胞老化 / 増殖応答 / 炎症応答 / 平滑筋細胞 / 組織破壊 / 組織修復 / 血管平滑筋細胞 / 炎症細胞 / 細胞増殖 / 炎症

Outline of Research at the Start

大動脈は心臓から全身に血液を送る人体で最大の血管である。大動脈解離は、この大動脈の壁が強い痛みとともに突然裂ける原因不明の病気である。大動脈解離が悪化し命に関わる場合は人工血管に入れ替える緊急手術が行われるが、死亡することも稀では無い。
細胞に過度のストレスが加わると、その細胞が老化することが知られている。老化した細胞は本来の働きを失い組織を維持できなくなることがある。申請者のこれまでの研究で、解離組織で細胞老化が起こっていると思われた。本研究では、マウス大動脈解離モデルとヒト大動脈解離組織を使って大動脈解離と細胞老化の関わりを解き明かすことで、病気の成り立ちを明らかにする。

Outline of Final Research Achievements

Aortic dissection (AD) is a fatal disease of unknown cause. In this study, we found that proliferation and senescence of various cell types occurred in a mouse AD model. Inhibiting the proliferative response with rapamycin also inhibited cell senescence and prevented AD. Administration of the senolytic reagent ABT-263 to mice inhibited the appearance of senescent cells and the onset and progression of AD. In the aortic wall after AD-inducing stimulation, IL-6 was expressed before the onset of AD, and the phenotype of smooth muscle cells changed from contractile to secretory, which was suppressed by ABT-263. We conclude that AD is caused by rapamycin-dependent proliferative responses and cellular senescence through destructive inflammatory responses and transformation of smooth muscle cells.

Academic Significance and Societal Importance of the Research Achievements

大動脈解離は前触れのない強烈な痛みとともに発症し、急速に重症化して突然死を引き起こす原因不明の病気である。現時点では病気の成り立ちは不明で発症は予想できず、発症後は緊急手術以外に積極的な治療法はない。マウスの大動脈解離モデルで検討したところ、解離の発症に先立って大動脈壁の細胞に異常増殖と老化が起こることがわかった。薬で老化した細胞を取り除くと大動脈解離の発症や重症化を抑制できることがわかった。この研究をもとに解離の発症予測や治療ができるようになるかもしれない。

Research Products

• [Journal Article] Ying and Yang of Stat3 in pathogenesis of aortic dissection (2021)
  • Author(s): Aoki Hiroki、Majima Ryohei、Hashimoto Yohei、Hirakata Saki、Ohno-Urabe Satoko
  • Journal Title: Journal of Cardiology Volume: 77 Issue: 5 Pages: 471-474
  • DOI: 10.1016/j.jjcc.2020.10.010
  • Peer Reviewed / Open Access
• [Journal Article] The Role of Syk in Inflammatory Response of Human Abdominal Aortic Aneurysm Tissue (2020)
  • Author(s): Kanamoto Ryo、Aoki Hiroki、Furusho Aya、Otsuka Hiroyuki、Shintani Yusuke、Tobinaga Satoru、Hiromatsu Shinichi、Fukumoto Yoshihiro、Tanaka Hiroyuki
  • Journal Title: Annals of Vascular Diseases Volume: 13 Issue: 2 Pages: 151-157
  • DOI: 10.3400/avd.oa.20-00009
  • NAID: 130007864379
  • ISSN: 1881-641X, 1881-6428
  • Year and Date: 2020-06-25
  • Peer Reviewed / Open Access
• [Journal Article] High Salt Intake Worsens Aortic Dissection in Mice (2020)
  • Author(s): Nishida Norifumi、Aoki Hiroki、Ohno-Urabe Satoko、Nishihara Michihide、Furusho Aya、Hirakata Saki、Hayashi Makiko、Ito Sohei、Yamada Hiroshi、Hirata Yuichiro、Yasukawa Hideo、Imaizumi Tsutomu、Tanaka Hiroyuki、Fukumoto Yoshihiro
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 40 Issue: 1 Pages: 189-205
  • DOI: 10.1161/atvbaha.119.313336
  • Peer Reviewed / Open Access
• [Journal Article] MRTF-A promotes angiotensin II-induced inflammatory response and aortic dissection in mice (2020)
  • Author(s): Ito Sohei、Hashimoto Yohei、Majima Ryohei、Nakao Eichi、Aoki Hiroki、Nishihara Michihide、Ohno-Urabe Satoko、Furusho Aya、Hirakata Saki、Nishida Norifumi、Hayashi Makiko、Kuwahara Koichiro、Fukumoto Yoshihiro
  • Journal Title: PLOS ONE Volume: 15 Issue: 3 Pages: e0229888-e0229888
  • DOI: 10.1371/journal.pone.0229888
  • Peer Reviewed / Open Access
• [Journal Article] Genetic Deletion of Socs3 in Smooth?Muscle Cells Ameliorates Aortic?Dissection in Mice (2020)
  • Author(s): Hirakata Saki、Aoki Hiroki、Ohno-Urabe Satoko、Nishihara Michihide、Furusho Aya、Nishida Norifumi、Ito Sohei、Hayashi Makiko、Yasukawa Hideo、Imaizumi Tsutomu、Hiromatsu Sinichi、Tanaka Hiroyuki、Fukumoto Yoshihiro
  • Journal Title: JACC: Basic to Translational Science Volume: 5 Issue: 2 Pages: 126-144
  • DOI: 10.1016/j.jacbts.2019.10.010
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic Effect of Rapamycin on Aortic Dissection in Mice (2020)
  • Author(s): Hayashi-Hori Makiko、Aoki Hiroki、Matsukuma Miho、Majima Ryohei、Hashimoto Yohei、Ito Sohei、Hirakata Saki、Nishida Norifumi、Furusho Aya、Ohno-Urabe Satoko、Fukumoto Yoshihiro
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 9 Pages: 3341-3341
  • DOI: 10.3390/ijms21093341
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] The role of cellular senescence in aortic dissection (2022)
  • Author(s): Nakao E, Aoki H, Majima R, Hashimoto Y, Shibata R, Hayashi M, Ohno-Urabe S, Furusho A, Norifumi N, Hirakata S, Fukumoto Y
  • Organizer: European Society for Cardiology Congress 2022
  • Int'l Joint Research
• [Presentation] The role of cellular senescence in aortic dissection (2022)
  • Author(s): Nakao E, Aoki H, Majima R, Hashimoto Y, Shibata R, Hayashi M, Ohno-Urabe S, Furusho A, Norifumi N, Hirakata S, Fukumoto Y
  • Organizer: American Heart Association Scientific Sessions 2022
  • Int'l Joint Research
• [Presentation] Diverse Role of Spleen Tyrosin Kinase (Syk) In Pathomechanism of Aortic Dissection (2022)
  • Author(s): Shibata R, Aoki H, Nakao E, Majima R, Hashimoto Y, Hayashi M, Ohno-Urabe S, Furusho A, Norifumi N, Hirakata S, Fukumoto Y
  • Organizer: American Heart Association Scientific Sessions 2022
  • Int'l Joint Research
• [Presentation] The role of Fak in murine model of aortic dissection (2022)
  • Author(s): Majima R, Aoki H, Hashimoto Y, Hayashi M, Ito S, Ohno-Urabe S, Fukumoto Y
  • Organizer: 第８６回日本循環器学会学術集会
• [Presentation] 大動脈壁の防御・破壊・修復機構 (2022)
  • Author(s): 青木浩樹
  • Organizer: 第50回日本血管外科学会学術総会
  • Invited
• [Presentation] 大動脈解離の分子病態：増殖応答から炎症応答まで (2022)
  • Author(s): 青木浩樹
  • Organizer: 第６３回日本脈管学会総会
  • Invited
• [Presentation] 大動脈解離病態における細胞老化の関与 (2022)
  • Author(s): 中尾英智、青木浩樹、眞島涼平、橋本洋平、柴田怜、林真貴子、大野-浦部聡子、古荘文、西田憲文、平方佐季、福本義弘
  • Organizer: 第133回日本循環器学会九州地方会
  • Invited
• [Presentation] 大動脈解離の病態 - 細胞増殖と老化応答 - (2022)
  • Author(s): 青木浩樹
  • Organizer: 第３回シロリムス新作用研究会
  • Invited
• [Presentation] Focal adhesion kinase promotes tissue destruction in aortic dissection in mice (2020)
  • Author(s): Majima R, Aoki H, Hashimoto Y, Hayashi M, Ito S, Ohno-Urabe S, Fukumoto Y
  • Organizer: Basic Cardiovascular Sciences Scientific Sessions 2020
  • Int'l Joint Research
• [Presentation] The role of B cells and IgG in aortic dissection (2020)
  • Author(s): Nishida N, Furusho A, Aoki H, Hirakata S, Ito S, Hayashi M, Hashimoto Y, Majima R, Fukumoto Y
  • Organizer: ESC Congress 2020
  • Int'l Joint Research
• [Presentation] Syk activation is a defense mechanism of aortic wall against aortic dissection (2020)
  • Author(s): Hashimoto Y, Aoki H, Majima R, Hayashi M, Nishida N, Ito S, Furusho A, Hirakata S, Ohno-Urabe S, Fukumoto Y
  • Organizer: ESC Congress 2020
  • Int'l Joint Research
• [Presentation] Regulation of Extracellular Matrix Metabolism in Aortic Dissection (2020)
  • Author(s): Nishida N, Aoki H, Ohno-Urabe S, Nishihara M, Furusho A, Hirakata S, Hayashi M, Ito S, Yasukawa H, Fukumoto Y
  • Organizer: 第84回日本循環器学会学術集会
  • Int'l Joint Research / Invited
• [Presentation] High salt and IL-17A cooperatively worsens aortic dissection in mice (2020)
  • Author(s): Nishida N, Aoki H, Ohno-Urabe S, Nishihara M, Furusho A, Hirakata S, Hayashi M, Ito S, Yasukawa H, Fukumoto Y
  • Organizer: 第84回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] FAK, a mechanosensitive kinase, promotes aortic dissection in mice (2020)
  • Author(s): Majima R, Aoki H, Hashimoto Y, Hayashi M, Ito S, Ohno-Urabe S, Fukumoto Y
  • Organizer: 第84回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] Syk activation is a defense mechanism of aortic wall against aortic dissection (2020)
  • Author(s): Hashimoto Y, Aoki H, Majima R, Hayashi M, Nishida N, Ito S, Furusho A, Hirakata S, Ohno-Urabe S, Fukumoto Y
  • Organizer: 第84回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] Syk activation is a defense mechanism in murine model of aortic dissection (2019)
  • Author(s): Y Hashimoto, H Aoki, R Majima, M Hayashi, S Ohno-Urabe, A Furusho, N Nishida, S Hirakata and Y Fukumoto
  • Organizer: ESC CONGRESS 2019
  • Int'l Joint Research
• [Presentation] Activation of focal adhesion kinase is involved in pathogenesis of aortic dissection in mice (2019)
  • Author(s): R Majima, H Aoki, Y Hashimoto, M Hayashi, S Ohno-Urabe, A Furusho, N Nishida, S Hirakata and Y Fukumoto
  • Organizer: ESC CONGRESS 2019
  • Int'l Joint Research
• [Presentation] The role of Spleen tyrosine kinase in human abdominal aortic aneurysm pathogenesis (2019)
  • Author(s): R Kanamoto, H Aok, A Furusho, H Otsuka, Y Shintani, S Tobinaga, S Hiromatsu, Y Fukumoto, H Tanaka
  • Organizer: ESC CONGRESS 2019
  • Int'l Joint Research
• [Presentation] Macrophage Overactivation Promotes Aortic Dissection Associated with Medial Expression of Arf and Impaired Proliferation of Smooth Muscle Cells in Mice (2019)
  • Author(s): S Ohno-Urabe, M Kase, H Aoki, M Nishihara, A Furusho, S Hirakata, N Nishida, S Ito, M Hayashi, Y Fukumoto
  • Organizer: Vascular Discovery: From Genes to Medicine Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] 大動脈解離の分子病態解明を目指して (2019)
  • Author(s): 青木浩樹
  • Organizer: 第６０回日本脈管学会総会
  • Invited
• [Presentation] 大動脈疾患における炎症応答の多面性 (2019)
  • Author(s): 青木浩樹
  • Organizer: 第47回日本血管外科学会
  • Invited
• [Presentation] 大動脈解離におけるストレス応答メカニズムと炎症 (2019)
  • Author(s): 青木浩樹
  • Organizer: 第19回日本NO学会学術集会
  • Invited
• [Presentation] Syk は大動脈解離抑制因子である (2019)
  • Author(s): 橋本洋平
  • Organizer: 第19回日本NO学会学術集会
• [Presentation] 大動脈解離の病因における FAK の関与 (2019)
  • Author(s): 眞島涼平
  • Organizer: 第19回日本NO学会学術集会