The role of protein lysine-acetlation in congenital heart disease

• 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
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• 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 / アセチル化修飾 / 心筋脂肪酸代謝 / 解糖系代謝 / 心肥大 / エネルギー代謝 / ミトコンドリア機能

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.

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

Research Products

• [Int'l Joint Research] University of Alberta(カナダ)
• [Int'l Joint Research] University of Alberta(Canada)
• [Journal Article] Branched-chain amino acid supplementation ameliorates angiotensin II-induced skeletal muscle atrophy. (2020)
  • Author(s): Yamanashi K, Kinugawa S, Fukushima A, Kakutani N, Takada S, Obata Y, Nakano I, Yokota T, Kitaura Y, Shimomura Y, Anzai T.
  • Journal Title: Life Sciences Volume: 250 Pages: 117593-117595
  • DOI: 10.1016/j.lfs.2020.117593
  • Peer Reviewed
• [Journal Article] Enhanced Echo Intensity of Skeletal Muscle Is Associated With Exercise Intolerance in Patients With Heart Failure (2019)
  • Author(s): Nakano Ippei、Hori Hiroaki、Fukushima Arata、Yokota Takashi、Kinugawa Shintaro、Takada Shingo、Yamanashi Katsuma、Obata Yoshikuni、Kitaura Yasuyuki、Kakutani Naoya、Abe Takahiro、Anzai Toshihisa
  • Journal Title: Journal of Cardiac Failure Volume: - Issue: 8 Pages: 30416-30419
  • DOI: 10.1016/j.cardfail.2019.09.001
  • Peer Reviewed
• [Journal Article] Acetylation contributes to hypertrophy-caused maturational delay of cardiac energy metabolism. (2018)
  • Author(s): Fukushima A, Zhang L, Huqi A, Lam VH, Rawat S, Altamimi T, Wagg CS, Dhaliwal KK, Hornberger LK, Kantor PF, Rebeyka IM, Lopaschuk GD.
  • Journal Title: JCI Insight Volume: 3(10) Issue: 10 Pages: 99239-99256
  • DOI: 10.1172/jci.insight.99239
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Cardiac hypertrophy in congenital heart disease delays the maturation of cardiac fatty acid β-oxidation by modifying myocardial acetylation control (2017)
  • Author(s): Fukushima A, Kingawa S, Yokota T, Takada S, Furihata T, Matsumoto J, Tsuda M, Nakajima T, Katayama T, Nanbu H, Maekawa S, Kakutani N, Shirakawa R, Okita K, Kantor PF, Rebeyka, IM, Lopaschuk GD
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] Protein acetylation in skeletal muscle impairs mitochondrial fatty acid oxidation and limits exercise capacity in post-infarct heart failure in mice. (2017)
  • Author(s): 山梨克真，津田正哉，福島 新，高田真吾，降旗高明，松本純一，前川 聡，片山貴史，横田 卓，絹川真太郎
  • Organizer: 第21回日本心不全学会学術集会
• [Presentation] Mitochondrial Protein Hyperacetylation in Skeletal Muscle is Associated with Exercise Intolerance in Murine Model of Post-Infarct Heart Failure (2017)
  • Author(s): Fukushima A, Tsuda M, Takada S, Yokota T, Saito A, Mizushima W, Furihata T, Matsumoto J, Katayama T, Nakajima T, Maekawa S, Nambu H, Shirakawa R, Kakutani N, Yoshikuni O, Yamanashi K, Okita K, and Kinugawa S
  • Organizer: 22nd International Academy of Cardiology Annual Scientific Sessions.
  • Int'l Joint Research
• [Presentation] Acetylation of mitochondrial proteins alters fatty acid β-oxidation in skeletal muscle and limits exercise capacity in post-infarct heart failure in mice. (2017)
  • Author(s): Masaya T, Fukushima A, Matsumoto J, Takada S, Yokota T, Furihata T, Katayama T, Nakajima T, Nambu H, Maekawa S, Shirakawa R, Kakutani N, Obata Y, Yamanashi K, Okita K, Kinugawa S
  • Organizer: American Heart Association Scientific Session
  • Int'l Joint Research
• [Funded Workshop] American Heart Association Scientific Session (2017)
• [Funded Workshop] International Academy of Cardiology Annual Scientific Sessions (2017)