Beta-arrestin-biased agonism of CXCR7 affects post-infarct cardiac remodeling.

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08510
• 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: The University of Tokyo
• Principal Investigator: Harada Mutsuo 東京大学, 医学部附属病院, 特任准教授 (90431642)
• Co-Investigator(Kenkyū-buntansha): 東口 治弘 東京大学, 医学部附属病院, 届出研究員 (40436358)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: CXCR7 / 心不全 / 心筋梗塞

Outline of Final Research Achievements

CXCR7 is a beta-arrestin-biased receptor highly expressed in the heart but its role remains elusive. Here we performed single cell-RNAseq analysis and revealed that Cxcr7 is predominantly expressed in cardiomyocytes, not in endothelial cells. Cardiomyocyte-specific Cxcr7 null mouse exhibited exercerbated heart morphology and function after myocardial infarction, suggesting the cardioprotective effects of CXCR7. in vitro study using CXCL12, a CXCR7 ligand, demonstrated that ERK activation is CXCL12 dose dependent. ERK activation was also observed in the border zone of infarcted murine heart and this ERC activation was abolished in cardiac-specific CXCR7 null heart. In human hearts, RNAseq analysis unveiled Cxcr7 expressions were significantly increased in failing heart compared to control heart and this increase was ameliorated by LVAD treatment, further suggesting the association of CXCR7 and heart failure.

Free Research Field

心不全

Academic Significance and Societal Importance of the Research Achievements

本研究においては、以下のような新規の発見があった。
①心臓においてCXCR7の発現量は高く、とくに心筋細胞がその首座になっていること、②心筋細胞内に発現するCXCR7が心筋梗塞に対して保護的にはたらくこと、③CXCR7がERKを介して心保護的に働くこと、④ヒト心臓においても同様の心保護効果が期待されること、である。心不全治療の標的分子として応用可能性が見いだされた。