The novel strategy for treating heart failure based on cardio-intestinal relationship; functional significance of endogenous GLP-1

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08032
• 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: Gifu University
• Principal Investigator: Kanamori Hiromitsu 岐阜大学, 医学部附属病院, 准教授 (20456502)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 心不全 / ミトコンドリアダイナミクス / オートファジー / 高血圧 / GLP-1 / GLP1受容体

Outline of Final Research Achievements

Plasma GLP-1 levels was increased from intestinal response to heart failure. The expression of myocardial GLP-1 receptor was augmented and its downstream signals such as PKA, CREB, DRP1) were phosphorylated in failing heart. Promotion of GLP-1 secretion by miglitol treatment augmented myocardial GLP-1R downstream signals, increased myocardial size by fusion and ATP production, and consequently, mitigated heart failure. On the other hand, GLP-1R with exendin(9-39) blockade brought about opposite results and aggravated cardiac dysfunction despite the increased GLP-1 synthesis. The present study suggests a concept, cardio-intestinal relationship; the intestine mediates a compensatory response to heart failure through GLP-1 synthesis and activation of its receptor system. It is important that enhancement endogenous GLP-1, which would augment mitochondrial fusion in cardiomyocytes via the PKA-DRP1 pathway, may be a novel therapeutic strategy for treating heart failure.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

現在心不全罹患者は急激に増加し心不全と他臓器との関連が注目されている。「心腸連関」は未だ確立されていないが、これまでに心不全動物モデルにおいてGLP-1の心保護作用に関する多くの報告があること、心筋にもGLP-1受容体の存在が証明されていることからGLP-1を軸として心臓と腸管に強い関連が想定される。GLP-1Rの下流には心筋エネルギー代謝に関わるシグナルがあるがここからつながるミトコンドリアダイナミクスやオートファジーとの関連は不明である。これらを明らかにすることは細胞生物学的に意義があると同時に新しい心不全治療法開発のブレイクスルーとなる可能性がある。