The role of circular RNA ITCH in the development of aortic stenosis

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15838
• 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): 2018-04-01 – 2021-03-31
• Keywords: ITCH E3 ligase / cardiac hypertrophy / aortic stenosis

Outline of Final Research Achievements

Left ventricular hypertrophy and aortic valve calcification are associated with the development of aortic stenosis. We examined the role of circular ITCH and ITCH on the development of aortic stenosis. Unexpectedly, expression level of miR214, a target of circular ITCH, was not changed after left ventricular hypertrophy induced by transverse aortic constriction. Thus, we focused on the ubiquitin E3 ligase ITCH, but not circular ITCH, and found that ITCH attenuates left ventricular hypertrophy through Wnt/β catenin signaling pathway. Furthermore, mRNA expression level of ITCH in aortic valve was lower in patients with AS than in those without it. These findings suggest a pivotal role of ITCH in the development of aortic stenosis and identify ITCH as a potential treatment target for preventing aortic stenosis.

Free Research Field

循環器領域

Academic Significance and Societal Importance of the Research Achievements

ユビキチン転移酵素ITCHが大動脈弁狭窄症発症(左室肥大や大動脈弁硬化)に関連することを示した。左室肥大に関しては、心筋特異的ITCH過剰発現マウスを用いて、ITCHがWnt/βカテニン経路を介して、野生型マウスに比較して心肥大を抑制し、心機能を改善することを示した。大動脈弁硬化に関しては、人大動脈弁サンプルを用いて、大動脈狭窄症の発症に、ITCHの機能低下が関与することを示した。また、ITCHがRunx2の発現を抑制するデータを得た。本研究により得られた新たな知見から、ITCHが左室肥大と大動脈弁硬化に対する新たな治療標的となりうる可能性が示唆された。