The role of protein lysine-acetlation in congenital heart disease

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K10137
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Hokkaido University
• Principal Investigator: FUKUSHIMA ARATA 北海道大学, 医学研究院, 客員研究員 (40706553)
• Co-Investigator(Kenkyū-buntansha): 絹川 真太郎 北海道大学, 医学研究院, 講師 (60399871) ; 高田 真吾 北海道大学, 医学研究院, 博士研究員 (60722329) ; 横田 卓 北海道大学, 大学病院, 特任講師 (90374321)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 先天性心疾患 / 心筋代謝 / 翻訳後修飾 / 心不全 / アセチル化 / 脂肪酸代謝

Outline of Final Research Achievements

We investigated the maturational changes in cardiac energy metabolism in congenital heart disease (CHD) with heart failure. The CHD model was created using newborn rabbits subjected to an aortocaval shunt. Decreased cardiac fatty acid oxidation along with decline in energy production occurred in CHD group compared to sham group. In addition, reduced acetylation, an important post-translational modification of proteins, of fatty acid β-oxidation enzymes, LCAD and β-HAD, was observed in CHD group, associated with reduced enzymatic activities and fatty acid oxidation rates. Of note, the expression of the mitochondrial acetyltransferase, GCN5L1, was reduced in CHD group, and silencing GCN5L1 mRNA in cultured cardiomyocytes (H9c2 cells) significantly reduced acetylation and activity of LCAD and β-HAD, leading to an overt cardiac hypertrophy. A similar phenomenon was also proved in studies using myocardial specimens of patients with congenital heart disease.

Free Research Field

循環器内科

Academic Significance and Societal Importance of the Research Achievements

診断や外科手術の目覚ましい進歩により小児先天性心疾患の出生後の予後は飛躍的に向上した。しかし、成人以降も心不全を合併し日常生活が著しく障害されるため病態解明が急務である。本研究は先天性心疾患における病的心肥大の分子基盤として、代謝酵素の翻訳後修飾であるアセチル化の減弱と、それに伴う脂肪酸代謝の成熟化遅延を同定した。アセチル化促進を標的とした新たな治療が先天性心疾患に合併する心不全に有効かもしれない