Mechanism of functional recovery of failing heart by histone modification in patients with LVAD

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08864
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55030:Cardiovascular surgery-related
• Research Institution: Osaka University
• Principal Investigator: Ito Emiko 大阪大学, 大学院医学系研究科, 招へい教員 (80595629)
• Co-Investigator(Kenkyū-buntansha): 河村 拓史 大阪大学, 大学院医学系研究科, 助教 (60839398)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 心不全 / 左室補助人工心臓 / unloading / ヒストンメチル化

Outline of Final Research Achievements

To develop a novel therapeutic approach for heart failure, in this study, we focused on relationship between H3K9 methylation and the functional recovery in failing heart by unloading with the left ventricular assist device (LVAD).
In human iPS cell-derived cardiomyocytes (hiPSC-CMs) cultured under hypoxia, the expression of H3K9 methylation tended to be less. To examine the mechanical effects on myocardial tissue in the heart, hiPSC-CMs were cultured under cyclic stretch in a stretch chamber. The H3K9 methylation in hiPSC-CMs were upregulated under stretch culture. Futhermore, the gene expression of SUV39H1, an H3K9 methyltransferase, was increased, and the gene expression of JMJD1A, 2A, and 2D, which are demethylases, was decreased. These results suggested that left ventricular unloading may enhance H3K9 methylation and contribute to left ventricular remodeling.

Free Research Field

心臓血管外科学

Academic Significance and Societal Importance of the Research Achievements

これまで多数の重症心不全患者に対して補助人工心臓を装着し術後の病状を観察していく中で、LVADを装着する事により左心室心筋構造および心機能改善が認められ、実際にこれまで複数症例でLVADからの永久離脱に成功している。しかし、LVAD装着によるunloadingによる心機能回復のメカニズムは多くが未だ不明のままである。
心不全心においてLVAD装着によるH3K9化学修飾とその転写制御のメカニズムが明らかとなれば、重症心不全のような重症化した心不全に対する新規治療法の開発に繋がる可能性があり、学術的・社会的意義は大きいと考えられる。