Molecular mechanism for after-load mismatch involved in the development of acute heart failure accompanied by chronic renal dysfunction

• Project/Area Number: 19H03659
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Nara Medical University
• Principal Investigator: Saito Yoshihiko 奈良県立医科大学, 医学部, 教授 (30250260)
• Co-Investigator(Kenkyū-buntansha): 尾上 健児 奈良県立医科大学, 医学部, 講師 (90510173) ; 熊澤 拓也 奈良県立医科大学, 医学部, 研究員 (10745441)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 急性心不全 / アフターロードミスマッチ / βアドレナリン受容体 / 脱感作 / 慢性腎臓病 / β1アドレナリン受容体 / LncRNA / 心不全 / sFlt-1 / β受容体脱感作 / GRK2 / Βarrestin 2 / ββ1アドレナリン受容体

Outline of Research at the Start

本研究では、急性心不全の発症病態の１つである急性の後負荷増大に対する不適合afterload mismatchの発症に、心臓と血管のβADR系の脱感作（心筋の収縮性低下と血管収縮を引き起こす）とLncRNA Xが関与しているか？さらに、両者の情報伝達系の連関を明らかにしCKD合併afterload mismatchの機序を解明する。

Outline of Final Research Achievements

Although afterload mismatch has been more widely recognized as one of the pathological conditions of acute heart failure than before, its molecular mechanism has not been clarified. Applicants found by using patient specimens that activation of β-adrenergic receptor (βADR) in myocardium and subsequent desensitization of βADR are involved in the development of Takotsubo syndrome, which is one of the causes of acute heart failure. With reference to this achievement, we proved the model mice which had the desensitization of βADR in blood vessels (causing contraction of blood vessels) developed afterload mismatch. This study is the first one in the world to prove that desensitization of the vascular endothelium causes an afterload mismatch.

Academic Significance and Societal Importance of the Research Achievements

我が国は、超高齢社会に突入するとともに、少子高齢化の影響を強く受け、今後、全人口は減少していくが、75歳以上人口のみは、今後20年間にわたり増加することが推測されている。この75歳以上の後期高齢者において、現在でも第1位の死因は脳卒中を含む循環器病であり（悪性腫瘍ではない）、中でも心不全の占める割合が今後増加することが確実視されている。本研究において、急性心不全の比較的頻繁に認められるafterload mismatchの分子機序を証明したことで、今後急性心不全予防のために、どのような治療的アプローチを取るべきかを見出していく重要なステップとなる。

Research Products

• [Journal Article] Value of Placental Growth Factor as a Predictor of Adverse Events During the Acute Phase of Acute Decompensated Heart Failure (2019)
  • Author(s): Nakada Y, Kawakami R, Matsui M, Ueda T, Nakano T, Nakagawa H, Nishida T, Onoue K, Soeda T, Okayama S, Watanabe M, Okura H, Saito Y.
  • Journal Title: Circulation Journal Volume: 83 Issue: 2 Pages: 395-400
  • DOI: 10.1253/circj.CJ-18-0523
  • NAID: 130007557048
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2019-01-25
  • Peer Reviewed / Open Access
• [Journal Article] AST-120, an Oral Carbon Absorbent, Protects against the Progression of Atherosclerosis in a Mouse Chronic Renal Failure Model by Preserving sFlt-1 Expression Levels. (2019)
  • Author(s): Nakada Y, Onoue K, Nakano T, Ishihara S, Kumazawa T, Nakagawa H, Ueda T, Nishida T, Soeda T, Okayama S, Watanabe M, Kawakami R, Saito Y.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 15571-15571
  • DOI: 10.1038/s41598-019-51292-9
  • Peer Reviewed / Open Access
• [Presentation] Molecular mechanism for cardio‐renal connection (2019)
  • Author(s): Yoshihiko Saito
  • Organizer: 2019 XXIII ISHR WORLD CONGRESS
  • Int'l Joint Research / Invited
• [Remarks] 奈良県立医科大学循環器内科ホームページ
  • URL: https://www.naramed-u.ac.jp/~1int/
• [Remarks] 奈良県立医科大学循環器内科学教室ホームページ
  • URL: http://www.naramed-u.ac.jp/~1int/index.html