Investigation of the role of the adaptive immunity in cardiovascular disease and development of therapeutic strategies

• Project/Area Number: 18K08088
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Kobe Pharmaceutical University
• Principal Investigator: Sasaki Naoto 神戸薬科大学, 薬学部, 准教授 (00514746)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 動脈硬化 / 大動脈瘤 / 心不全 / 炎症 / 免疫 / 高血圧

Outline of Final Research Achievements

Immunoinflammatory responses are critically involved in the development of atherosclerotic cardiovascular diseases. Using various mouse models of atherosclerotic diseases, we identified a novel target and an immunomodulatory strategy to prevent these diseases. We reported that the immunoregulatory molecule cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in limiting the development of abdominal aortic aneurysm by suppressing aortic immunoinflammatory responses. Ultraviolet B (UVB) irradiation is known to dampen immunoinflammatory reactions. We found that broad-band UVB irradiation inhibits the onset and development of heart failure associated with myocardial infarction. We also identified UVB wavelengths effective in preventing atherosclerosis.

Academic Significance and Societal Importance of the Research Achievements

我が国での動脈硬化性疾患は、癌についで死亡原因の第２位となっており、その発症機序の解明や有効な治療・予防法の開発が切に望まれている。大動脈瘤には外科的治療が行われるが、合併症のリスクが高く、非侵襲的な治療法の開発が必要である。本研究で見出したCTLA-4の機能を模倣した薬剤は、関節リウマチの治療に用いられており、大動脈瘤の治療への応用が期待される。UVB療法は、経済的負担が少なく安全な治療法として皮膚科領域で臨床応用されている。近年、動脈硬化性疾患に対する治療は医療経済を圧迫しているが、UVB療法は経済的負担の少ない治療法として期待され、新規治療法として臨床応用を実現したい。

Research Products

• [Journal Article] Cytotoxic T Lymphocyte-Associated Antigen-4 Protects Against Angiotensin II-Induced Kidney Injury in Mice (2020)
  • Author(s): Amin HZ, Sasaki N, Hirata KI, Rikitake Y.
  • Journal Title: Circulation Reports Volume: 2 Issue: 6 Pages: 339-342
  • DOI: 10.1253/circrep.CR-20-0023
  • NAID: 130007853617
  • ISSN: 2434-0790
  • Year and Date: 2020-06-10
  • Peer Reviewed / Open Access
• [Journal Article] CTLA-4 Protects against Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice. (2019)
  • Author(s): Amin HZ, Sasaki N, Yamashita T, Mizoguchi T, Hayashi T, Emoto T, Matsumoto T, Yoshida N, Tabata T, Horibe S, Kawauchi S, Rikitake Y, Hirata KI
  • Journal Title: Scientific Reports Volume: 9(1) Issue: 1 Pages: 8065-8065
  • DOI: 10.1038/s41598-019-44523-6
  • NAID: 120006645700
  • Peer Reviewed / Open Access
• [Journal Article] Possible beneficial effects of narrow-band UVB therapy on hypertension and vitamin D levels in patients with cutaneous disease. (2019)
  • Author(s): Emoto T, Sasaki N, Yamashita T, Fukunaga A, Masaki T, Nishigori C, Hirata KI
  • Journal Title: Photomedicine and Photobiology Volume: 40 Pages: 17-22
  • Peer Reviewed
• [Journal Article] Ultraviolet B irradiation as a novel strategy to prevent atherosclerotic cardiovascular disease. (2018)
  • Author(s): Sasaki N
  • Journal Title: Photomedicine and Photobiology Volume: 39 Pages: 7-15
  • Peer Reviewed
• [Presentation] 特定の紫外線B波照射による動脈硬化抑制効果の検討 (2021)
  • Author(s): 佐々木直人、福永淳、錦織千佳子、力武良行
  • Organizer: 第42回日本光医学・光生物学会
• [Presentation] 特定波長の紫外線B波による動脈硬化抑制効果とその機序の解明 (2021)
  • Author(s): 田中亨、佐々木直人、西村紗良、井戸花乃、山口悠馬、武岡侑希、中村百花、浜田悠花、Amin Hilman Zulkifli、堀部紗世、平田健一、力武良行
  • Organizer: 日本薬学会第141年会
• [Presentation] Development of novel LED phototherapy to limit atherosclerosis. (2021)
  • Author(s): Hilman Zulkifli Amin, Naoto Sasaki, Yoshiyuki Rikitake
  • Organizer: 第85回日本循環器学会学術集会
• [Presentation] Protective T-cell Immunity as an Attractive Therapeutic Target for Atherosclerotic Disease. (2020)
  • Author(s): Naoto Sasaki, Hilman Zulkifli Amin, Yoshiyuki Rikitake
  • Organizer: 第52回日本動脈硬化学会総会
• [Presentation] Selective C-C chemokine receptor 4 inhibition aggravates atherosclerosis in apolipoprotein E-deficient mice. (2020)
  • Author(s): Hilman Zulkifli Amin, Naoto Sasaki, Ken-ichi Hirata, Yoshiyuki Rikitake
  • Organizer: 第84回日本循環器学会学術集会
• [Presentation] Pharmacological inhibition of C-C chemokine receptor 4 aggravates atherosclerosis through prevention of regulatory T cell recruitment to the lesions. (2020)
  • Author(s): Hilman Zulkifli Amin, Naoto Sasaki, Sayo Horibe, Shoji Kawauchi, Ken-ichi Hirata, Yoshiyuki Rikitake
  • Organizer: European Society of Cardiology Congress, 2020
  • Int'l Joint Research
• [Presentation] 動脈硬化モデルマウスにおける病変形成抑制に有効な紫外線B波の波長の特定 (2020)
  • Author(s): 大内友梨香、佐々木直人、有地珠里、嶋本美咲、野口恵美、Hilman Zulkifli Amin、堀部紗世、河内正二、平田健一、力武良行
  • Organizer: 日本薬学会第140年会
• [Presentation] 動脈硬化性疾患に対する新規免疫療法の開発 (2019)
  • Author(s): 佐々木直人、力武良行
  • Organizer: 第51回日本動脈硬化学会総会
• [Presentation] 紫外線を用いた新規心血管疾患治療法の開発 (2019)
  • Author(s): 佐々木直人、福永淳、錦織千佳子、力武 良行
  • Organizer: 第39回日本光医学・光生物学会
• [Presentation] Overexpression of cytotoxic T-lymphocyte-associated antigen-4 suppresses aortic immunoinflammatory responses and prevents angiotensin II-induced abdominal aortic aneurysm formation in mice. (2019)
  • Author(s): Hilman Zulkifli Amin, Naoto Sasaki, Tomoya Yamashita, Taiji Mizoguchi, Tomohiro Hayashi, Takuo Emoto, Takuya Matsumoto, Naofumi Yoshida, Tokiko Tabata, Sayo Horibe, Shoji Kawauchi, Yoshiyuki Rikitake, Ken-ichi, Hirata
  • Organizer: European Society of Cardiology Congress, 2019
  • Int'l Joint Research
• [Presentation] Overexpression of cytotoxic T-lymphocyte-associated antigen-4 suppresses aortic immunoinflammatory responses and prevents angiotensin II-induced abdominal aortic aneurysm formation in mice. (2019)
  • Author(s): Hilman Zulkifli Amin, Naoto Sasaki, Tomoya Yamashita, Taiji Mizoguchi, Tomohiro Hayashi, Takuo Emoto, Takuya Matsumoto, Naofumi Yoshida, Tokiko Tabata, Sayo Horibe, Shoji Kawauchi, Yoshiyuki Rikitake, Ken-ichi, Hirata
  • Organizer: European Society of Cardiology Asia Congress 2019
  • Int'l Joint Research / Invited
• [Presentation] 共抑制分子CTLA-4はアンジオテンシンⅡ誘導性マウス腹部大動脈瘤の形成を抑制する (2019)
  • Author(s): 佐々木直人、Hilman Zulkifli Amin、堀部紗世、河内正二、平田健一、力武良行
  • Organizer: 日本薬学会第139年会
• [Presentation] Immune Checkpoint Proteins and Regulatory T Cells as Critical Immune Modulators in Atherosclerotic Disease and Cancer. (2019)
  • Author(s): Naoto Sasaki, Hilman Zulkifli Amin, Yoshiyuki Rikitake
  • Organizer: 第83回日本循環器学会学術集会
• [Presentation] Overexpression of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) protects against abdominal aortic aneurysm formation in mice. (2019)
  • Author(s): Hilman Zulkifli Amin, Naoto Sasaki, Tomoya Yamashita, Taiji Mizoguchi, Tomohiro Hayashi, Takuo Emoto, Takuya Matsumoto, Naofumi Yoshida, Tokiko Tabata, Sayo Horibe, Shoji Kawauchi, Yoshiyuki Rikitake, Ken-ichi Hirata
  • Organizer: 第83回日本循環器学会学術集会
  • Invited
• [Presentation] 動脈硬化性疾患とがんにおける免疫チェックポイントタンパク質と制御性T細胞の役割 (2018)
  • Author(s): 佐々木直人、山下智也、平田健一、力武良行
  • Organizer: 第50回日本動脈硬化学会総会
• [Presentation] 紫外線照射による心血管疾患発症・進展の抑制機序の検討と臨床応用 (2018)
  • Author(s): 佐々木直人、福永淳、錦織千佳子、山下智也、平田健一、力武良行
  • Organizer: 第40回日本光医学・光生物学会
  • Invited
• [Presentation] Treating atherosclerotic disease by modulating T cell immune responses. (2018)
  • Author(s): Naoto Sasaki
  • Organizer: XVIIIth International Symposium on Atherosclerosis
  • Int'l Joint Research / Invited
• [Presentation] Overexpression of cytotoxic T-lymphocyte-associated antigen-4 protects against abdominal aortic aneurysm formation in mice. (2018)
  • Author(s): Hilman Zulkifli Amin, Naoto Sasaki, Tomoya Yamashita, Taiji Mizoguchi, Yoshiyuki Rikitake, Ken-ichi, Hirata
  • Organizer: The 90th AHA Scientific Sessions
  • Int'l Joint Research
• [Presentation] CTLA-4 protects against experimental abdominal aortic aneurysm formation. (2018)
  • Author(s): Naoto Sasaki
  • Organizer: 第47回日本免疫学会学術集会
• [Book] 医学のあゆみ (2019)
  • Author(s): 佐々木 直人
  • Total Pages: 251
  • Publisher: 医歯薬出版株式会社
• [Remarks] 神戸大学薬科大学 医療薬学研究室
  • URL: https://www.kobepharma-u.ac.jp/edrs/faculty_member_list/medical_pharmaceutics.html