Therapeutic inhibition of microRNA-34a ameliorates aortic valve calcification via modulation of Notch1-Runx2 signaling

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09490
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Yamagata University
• Principal Investigator: WATANABE Tetsu 山形大学, 医学部, 准教授 (40359568)
• Research Collaborator: TOSHIMA Taku
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 石灰化大動脈弁狭窄症 / micro RNA / Notch1 / Runx2

Outline of Final Research Achievements

Expression of microRNA (miR)-23a, miR-34a, miR-34c, miR-133a, miR-146a, and miR-155 was increased, and expression of miR-27a and miR-204a was decreased in valve tissues from calcific aortic valve stenosis (CAVS) compared with those from aortic regurgitation (AR). Expression of Notch1 was decreased, and expression of Runt-related transcription factor 2 (Runx2) was increased in patients with CAVS compared with those with AR. We selected miR-34a among increased miRs in porcine aortic valve interstitial cells (AVICs) after osteogenic treatment. Inhibition of miR-34a significantly attenuated the calcification signals in AVICs compared with miR-control. In wire injury CAVS mice, locked nucleic acid miR-34a inhibitor suppressed aortic velocity, calcium deposition of aortic valves, and cardiac hypertrophy, which were involved in decreased Runx2 and increased Notch1 expressions.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

ヒト大動脈弁組織、ブタ大動脈弁間質細胞、ワイヤー傷害大動脈弁狭窄症マウスを用い、大動脈弁狭窄症の進展に深く関わるmiRの役割について検討した。先天性二尖弁は三尖に比べ、大動脈弁狭窄症の進行が速いが、これには組織反応障害仮説の関与が示唆される。既に癌治療の分野では、miRNAを用いた臨床試験が始まっている。またmiRsはバイオマーカーとしての応用も行われている。大動脈弁石灰化に密接に関わるmiRNAの同定は、ハイリスク患者の早期発見および治療介入に臨床応用できる可能性が期待できる。