Plexin B1 Exacerbates Cardiac Hypertrophy and Heart Failure

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K16076
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Yamagata University
• Principal Investigator: Yoichiro Otaki 山形大学, 医学部, 助教 (80732693)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: Plexin B1 / Sema4D / Cardiac hypertrophy / Heart Failure / BMAL1

Outline of Final Research Achievements

It remains undetermined whether Semaphorin-Plexin pathway play the key role in the development of HF. We focused on Plexin B1, a major receptor for Sema4D, and examined the functional role of Sema4D-Plexin B1 pathway in the development of HF. We established cardiac-specific Plexin B1 transgenic mice (Plexin B1-Tg). We performed thoracic transverse aortic constriction (TAC) in Plexin B1-Tg mice and their littermates. Immunoprecipitation confirmed the interaction between plexin B1 and Sema 4D in cardiac tissues. Plexin B1-Tg mice exhibited cardiac hypertrophy, exacerbated cardiac function, and lower survival rate compared with the WT mice after TAC. RNA sequencing of the cardiac tissues identified Bmal1 as the downregulated differentially expressed gene in Plexin B1-Tg compared to WT mice hearts. Overexpression of Plexin B1 augmented phosphorylation of Akt in cardiomyocytes. Plexin B1 mediates Bmal1/Akt signaling. Sema4D-Plexin B1 pathway can serve as a novel therapeutic target for HF.

Free Research Field

Cardiology

Academic Significance and Societal Importance of the Research Achievements

医学の進歩にも関わらず、心肥大と心不全は日本人の重要な死因である。そのため、新たな機序解明や治療薬の開発が期待される。我々は、Sema4D-Plexin B1 pathwayが、病的心肥大と心不全発症において重要な役割を担っていることをin vivoとin vitroの実験型で示した。分子生物学的には、Sema4D-Plexin B1 pathwayが時計遺伝子と関連する知見を得た。近年、抗Sema4D抗体が認知症での治療薬として注目されている。我々の結果は、心不全領域において、Sema4D-Plexin B1 pathwayが新たな治療標的となりうる可能生を示した。