Elucidation of myocardial energy metabolism via beta-3 receptor in sepsis

• Project/Area Number: 18K08879
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55060:Emergency medicine-related
• Research Institution: Asahikawa Medical College
• Principal Investigator: Okada Motoi 旭川医科大学, 医学部, 准教授 (80431427)
• Co-Investigator(Kenkyū-buntansha): 藤田 智 旭川医科大学, 医学部, 名誉教授 (10173428) ; 井尻 えり子 旭川医科大学, 大学病院, 助教 (40646072) ; 川口 哲 旭川医科大学, 医学部, 助教 (60814217)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 敗血症 / 心不全 / β３受容体 / エンドトキシン / ミトコンドリア / NO産生 / 心筋代謝 / LPS / 敗血症性心筋症 / メタボリックシフト

Outline of Final Research Achievements

In this study, we generated a mouse model of endotoxin (LPS)-induced heart failure, in which the myocardium is found to have increased expression of β3 receptors. The model showed a rapid decline in cardiac function and increased mortality, but administration of a β3 receptor antagonist restored cardiac function and prognosis, as well as reduced myocardial ATP levels. The mechanism for this was found to be abnormal transport of fatty acids into the mitochondria, although their uptake into the myocardium was preserved. Furthermore, inhibition of β3 receptors suppressed NFkB-mediated cytokine production, such as IL-6, and the induction of iNOS.

Academic Significance and Societal Importance of the Research Achievements

予後不良疾患である敗血症による心不全の病態において、エンドトキシンによる心不全もでるでは、β3受容体を制御することで、心機能や生命予後を改善することが確認された。このことは、β３受容体が敗血症性心筋症への治療ターゲットになる可能性があると考えられる。

Research Products

• [Journal Article] Cardiac Metabolism in Sepsis (2021)
  • Author(s): Kawaguchi Satoshi、Okada Motoi
  • Journal Title: Metabolites Volume: 11 Issue: 12 Pages: 846-846
  • DOI: 10.3390/metabo11120846
  • Peer Reviewed / Open Access
• [Journal Article] β(3)-Adrenergic receptor blockade reduces mortality in endotoxin-induced heart failure by suppressing induced nitric oxide synthase and saving cardiac metabolism. (2020)
  • Author(s): 1)Kawaguchi S, Okada M, Ijiri E, Koga D, Watanabe T, Hayashi K, Kashiwagi Y, Fujita S, Hasebe N.
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: 318 Issue: 2 Pages: H283-H294
  • DOI: 10.1152/ajpheart.00108.2019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 敗血症での心機能低下における小胞体―ミトコンドリア機能不全の関与 (2020)
  • Author(s): 岡田 基
  • Organizer: 日本救急医学会
• [Presentation] Cardiac Metabolism Was Improved by Regulation of Nitric Oxide Synthases Through the Beta-3 Adrenergic Receptor in Endotoxin-induced Failing Heart (2019)
  • Author(s): Okada M
  • Organizer: American Heart Assosiation
  • Int'l Joint Research
• [Book] 心血管系システムとβ３受容体 (2021)
  • Author(s): 岡田 基
  • Total Pages: 2
  • Publisher: 医歯薬出版株式会社
• [Book] β遮断薬の日米欧ガイドラインにおける位置づけとエビデンス：敗血症 (2021)
  • Author(s): 岡田 基
  • Total Pages: 6
  • Publisher: 南山堂
• [Book] ショックとβレセプター：β３受容体と敗血症についての考察 (2019)
  • Author(s): 岡田 基
  • Total Pages: 8
  • Publisher: 総合医学社
  • ISBN: 9784883785568