Investigation for the role of hypoxic responses in mitochondrial dysfunction in heart failure

• Project/Area Number: 18K15892
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Kyushu University
• Principal Investigator: IKEDA MASATAKA 九州大学, 医学研究院, 特任助教 (10567382)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 虚血性心臓病 / 虚血再灌流傷害 / 低酸素誘導因子 / Hif-1α / ミトコンドリア / 酸素消費量 / 心血管病 / PHD阻害剤 / p53 / フェロトーシス / 活性酸素 / 低酸素応答 / 慢性心不全 / 心不全 / ミトコンドリア機能 / ミトコンドリア生合成 / ミトコンドリア機能不全

Outline of Final Research Achievements

In this study, we investigated the suppressive effect of hypoxia-inducible factor-1 (Hif-1α) using roxadustat, which is a first-in-class prolyl hydroxylase domain-containing protein (PHD) inhibitor, on an oxygen consumption in cardiomyocytes and infarct size in a murine ischemic/reperfusion model. The treatment with roxadustat in isolated cardiomyocytes significantly lowers an oxygen consumption in mitochondria, and suppressed cell death induced by hypoxia/reoxygenation. Notably, the pretreatment with roxadustat markedly suppressed infarct size in a murine ischemia reperfusion model. Roxadustat will be a new therapeutic strategy against ischemic heart disease by lowering an oxygen consumption and thereby producing an ischemic tolerance.

Academic Significance and Societal Importance of the Research Achievements

低酸素誘導因子（Hif）を分解するプロリル水酸化酵素の阻害により腎性貧血を治療することを目的として開発されたfirst-in-classの薬剤であるroxadustatを用いることで、薬理学的に酸素代謝を抑制し、虚血耐性を誘導し得ることを明らかにした。本機序を利用することで、虚血性心疾患のみならず、心臓外科手術時（体外循環中）や臓器移植の際の臓器保護への応用も検討されることから、本薬剤の幅広い臨床応用の可能性が示唆された。

Research Products

• [Journal Article] Heart Rate Reduction with Ivabradine Prevents Cardiac Rupture after Myocardial Infarction in Mice (2021)
  • Author(s): Ikeda Masataka、Ide Tomomi、Furusawa Shun、Ishimaru Kosei、Tadokoro Tomonori、Miyamoto Hiroko Deguchi、Ikeda Soichiro、Okabe Kosuke、Ishikita Akihito、Abe Ko、Matsushima Shouji、Tsutsui Hiroyuki
  • Journal Title: Cardiovascular Drugs and Therapy Volume: - Issue: 2 Pages: 257-262
  • DOI: 10.1007/s10557-020-07123-5
  • Peer Reviewed / Open Access
• [Journal Article] Roxadustat Markedly Reduces Myocardial Ischemia Reperfusion Injury in Mice (2020)
  • Author(s): Deguchi H, Ikeda M, Ide T, Tadokoro T, Ikeda S, Okabe K, Ishikita A, Saku K, Matsushima S, Tsutsui H.
  • Journal Title: Circulation Journal Volume: 84 Issue: 6 Pages: 1028-1033
  • DOI: 10.1253/circj.CJ-19-1039
  • NAID: 130007846233
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2020-05-25
  • 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] 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] 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
• [Presentation] Mitochondria-dependent ferroptosis is the predominant regulated cell death in doxorubicin-induced 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
  • Organizer: 第84回 日本循環器学会学術集会
• [Presentation] ミトコンドリア誘導性フェロトーシスはドキソルビシン心筋傷害における主要な制御性細胞死である (2020)
  • Author(s): 田所 知命, 池田 昌隆, 井手 友美, 出口 裕子, 池田 宗一郎, 岡部 浩祐, 石北 陽仁, 松島 将士, 幸村 知子, 山田 健一, 今井 浩孝, 筒井 裕之
  • Organizer: 第6回日本心筋症研究会
• [Presentation] Ivabradineによる心拍数抑制は心筋梗塞境界部のHif-1α-p53の抑制を介して梗塞後新破裂を予防する (2019)
  • Author(s): 池田昌隆、井手友美、松島将士、田所知命、出口裕子、池田宗一郎、岡部浩祐、石北陽仁、筒井裕之
  • Organizer: 第126回日本循環器学会九州地方会
• [Presentation] Ferrptosis is the predominant regulated cell death in doxorubicin-induced cardiomyopathy (DIC) (2019)
  • 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
  • Organizer: 第23回日本心不全学会
• [Presentation] 新規PHD阻害剤であるRoxadustatはマウスにおける心筋虚血再灌流傷害を軽減する (2019)
  • Author(s): 出口裕子、池田昌隆、井手友美、田所知命、松島将士、池田宗一郎、岡部浩祐、石北陽仁、山本泰史、円山信之、佐田政司、筒井裕之
  • Organizer: 第127回日本循環器学会九州地方会
• [Presentation] Excessive Hif-1α induces cardiac rupture after myocardial infarction through p53-induced apoptosis (2019)
  • Author(s): Masataka Ikeda, Tomomi Ide, Shouji Matsushima, Tomonori Tadokoro, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Hiroyuki Tsutsui
  • Organizer: 第83回 日本循環器学会学術集会
• [Presentation] Ferroptosis plays a major role in the development of doxorubicin-induced cardiomyopathy (2019)
  • Author(s): Tomonori Tadokoro, Masataka Ikeda, Tomomi Ide, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Shouji Matsushima, Hiroyuki Tsutsui
  • Organizer: 第83回 日本循環器学会学術集会
• [Presentation] Excessive Hif-1α induces cardiac rupture after myocardial infarction through p53-induced apoptosis (2018)
  • Author(s): Masataka Ikeda, Tomomi Ide, Shouji Matsushima, Tomonori Tadokoro, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Hiroyuki Tsutsui
  • Organizer: 第35回 国際心臓研究会（ISHR）日本部会
• [Presentation] Ferroptosis plays a major role in the development of doxorubicin-induced cardiomyopathy (2018)
  • Author(s): Tomonori Tadokoro, Masataka Ikeda, Tomomi Ide, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Shouji Matsushima, Hiroyuki Tsutsui
  • Organizer: 第35回 国際心臓研究会（ISHR）日本部会
• [Book] 日本臨牀 76巻 増刊号9 心不全（第2版）上 ー最新の基礎・臨床研究の進歩ー (2018)
  • Author(s): 池田昌隆、井手友美、松島将士、筒井裕之
  • Total Pages: 720
  • Publisher: 日本臨牀社
• [Remarks] 九州大学 循環器内科
  • URL: https://www.cardiol.med.kyushu-u.ac.jp/
• [Remarks] 九州大学循環器内科研究グループ、心不全
  • URL: https://www.cardiol.med.kyushu-u.ac.jp/research/heart-failure/