Regulation of mitochondrial redox by sulfiredoxin in cardiac remodeling

• Project/Area Number: 19H03655
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Kyushu University
• Principal Investigator: Tsutsui Hiroyuki 九州大学, 医学研究院, 教授 (70264017)
• Co-Investigator(Kenkyū-buntansha): 康 東天 九州大学, 医学研究院, 教授 (80214716) ; 松島 将士 九州大学, 大学病院, 助教 (80552869) ; 井手 友美 九州大学, 医学研究院, 准教授 (90380625) ; 西村 明幸 九州大学, 薬学研究院, 講師 (00457152)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2021: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2019: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: 心不全 / スルフィレドキシン / 酸化ストレス / ミトコンドリア / 心筋リモデリング / 循環器内科学 / レドックス制御 / 死人リモデリング

Outline of Research at the Start

心不全の病態基盤である心筋リモデリングの形成・進展には心筋細胞のミトコンドリアの酸化ストレスが密接に関与している。スルフィレドキシン（SRX）は、不活性型ペルオキシレドキシン（Prx）を還元し蛋白グルタチオン化を制御する酵素であり、心筋細胞のミトコンドリアレドックス制御の基盤分子と考えられる。本研究は心筋リモデリングにおけるSRXのミトコンドリアレッドクス制御の意義を解明し、SRX機能安定化によるレドックス適正化を介したミトコンドリア機能の保持という独自のパラダイムに基づく新たな心不全の予防・治療法の開発を目指すものである。

Outline of Final Research Achievements

Sulfiredoxin was transiently increased and decreased in chronic phase after pressure overload, accompanied by an increase in protein carbonylation. SRX knockout mice showed development of LV remodeling and an increase in protein carbonylation and cleaved caspase 3. In cultured cardiomyocytes, SRX knockdown enhanced H2O2-induced mitochondrial dysfunction. On the other hand, cardiac-specific SRX overexpression mice exhibited attenuation of LV remodeling. Furthermore, these changes were accompanied by suppression of oxidative stress and cell death signaling.

Academic Significance and Societal Importance of the Research Achievements

本研究からSRXは心不全の進展過程において相対的に低下をきたし、その低下により心筋細胞の酸化ストレス、ミトコンドリア機能障害、アポトーシスを引き起こして心筋リモデリングの発症・進展に関与することが示された。SRXが新たな心不全治療ターゲットになるうることが示唆された。

Research Products

• [Journal Article] GFAT2 mediates cardiac hypertrophy through HBP-O-GlcNAcylation-Akt pathway (2021)
  • Author(s): Ishikita Akihito、Matsushima Shouji、Ikeda Soichiro、Okabe Kosuke、Nishimura Ryohei、Tadokoro Tomonori、Enzan Nobuyuki、Yamamoto Taishi、Sada Masashi、Tsutsui Yoshitomo、Miyake Ryo、Ikeda Masataka、Ide Tomomi、Kinugawa Shintaro、Tsutsui Hiroyuki
  • Journal Title: iScience Volume: 24 Issue: 12 Pages: 103517-103517
  • DOI: 10.1016/j.isci.2021.103517
  • Peer Reviewed / Open Access
• [Journal Article] Excessive Hypoxia‐Inducible Factor‐1α Expression Induces Cardiac Rupture via p53‐Dependent Apoptosis After Myocardial Infarction (2021)
  • Author(s): Ikeda Masataka、Ide Tomomi、Tadokoro Tomonori、Miyamoto Hiroko Deguchi、Ikeda Soichiro、Okabe Kosuke、Ishikita Akihito、Sato Midori、Abe Ko、Furusawa Shun、Ishimaru Kosei、Matsushima Shouji、Tsutsui Hiroyuki
  • Journal Title: Journal of the American Heart Association Volume: 10 Issue: 17 Pages: 1-15
  • DOI: 10.1161/jaha.121.020895
  • Peer Reviewed / Open Access
• [Journal Article] Cardiac-specific loss of mitoNEET expression is linked with age-related heart failure (2021)
  • Author(s): Furihata T, Takada S, Kakutani N, Maekawa S, Tsuda M, Matsumoto J, Mizushima W, Fukushima A, Yokota T, Enzan N, Matsushima S, Handa H, Fumoto Y, Nio-Kobayashi J, Iwanaga T, Tanaka S, Tsutsui H, Sabe H, Kinugawa S.
  • Journal Title: Commun Biol. Volume: 4 Issue: 1 Pages: 138-138
  • DOI: 10.1038/s42003-021-01675-4
  • Peer Reviewed / Open Access
• [Journal Article] DPP (Dipeptidyl Peptidase)-4 Inhibitor Attenuates Ang II (Angiotensin II)?Induced Cardiac Hypertrophy via GLP (Glucagon-Like Peptide)-1?Dependent Suppression of Nox (Nicotinamide Adenine Dinucleotide Phosphate Oxidase) 4-HDAC (Histone Deacetylase) 4 Pathway (2020)
  • Author(s): Okabe Kosuke、Matsushima Shouji、Ikeda Soichiro、Ikeda Masataka、Ishikita Akihito、Tadokoro Tomonori、Enzan Nobuyuki、Yamamoto Taishi、Sada Masashi、Deguchi Hiroko、Shinohara Keisuke、Ide Tomomi、Tsutsui Hiroyuki
  • Journal Title: Hypertension Volume: 75 Issue: 4 Pages: 991-1001
  • DOI: 10.1161/hypertensionaha.119.14400
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity (2020)
  • Author(s): Tomonori Tadokoro, Masataka Ikeda, Tomomi Ide, Hiroko Deguchi, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Shouji Matsushima, Tomoko Koumura, Ken-ichi Yamada, Hirotaka Imai, Hiroyuki Tsutsui
  • Journal Title: JCI insight Volume: 5 Issue: 9
  • DOI: 10.1172/jci.insight.132747
  • Peer Reviewed / Open Access
• [Journal Article] Blockade of L-type Ca2+ channel attenuates doxorubicin-induced cardiomyopathy via suppression of CaMKII-NF-κB pathway. (2019)
  • Author(s): Ikeda S, Matsushima S, Okabe K, Ikeda M, Ishikita A, Tadokoro T, Enzan N, Yamamoto T, Sada M, Deguchi H, Morimoto S, Ide T, Tsutsui H
  • Journal Title: Scientific reports Volume: 9 Issue: 1 Pages: 1-14
  • DOI: 10.1038/s41598-019-46367-6
  • Peer Reviewed / Open Access