Elucidation of the molecular mechanism of cardiac energy metabolism for the development of novel therapy for heart failure

• Project/Area Number: 16K09501
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Osaka University
• Principal Investigator: Kioka Hidetaka 大阪大学, 医学系研究科, 助教 (70642099)
• Co-Investigator(Kenkyū-buntansha): 坂田 泰史 大阪大学, 医学系研究科, 教授 (00397671)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: エネルギー代謝 / ミトコンドリア / ATP / 低酸素 / イメージング / 心不全

Outline of Final Research Achievements

Heart consumes large amount of ATP. ATP is generated through mitochondrial oxidative phosphorylation (OXPHOS) and oxygen is essential in this system. It has been known that energy impairment is involved in heart failure. In this study, we examined whether G0s2, which we identified as an activator of OXPHOS, protect tissue function for the development of novel therapy for heart failure. By establishing both gain of function and loss of function model of G0s2 in zebrafish, we demonstrated that G0s2 protect tissue function against hypoxia.　Our findings suggests that G0s2 could become a therapeutic target for energy impairment-related diseases such as heart failure.

Academic Significance and Societal Importance of the Research Achievements

心不全にエネルギー代謝不全が関与している事が知られているが、現在治療薬として用いられているβ遮断薬、ACE阻害薬は、エネルギー消費を抑制することで心不全予後を改善していると考えられている。しかし、今尚これらの薬物治療に抵抗性を示す難治性心不全があるようにその効果は不十分であり、ATP産生そのものを増やすことによりエネルギー状態を改善させる臓器保護薬の開発が求められる。本研究により、以前に我々が細胞実験によりミトコンドリアATP産生を増強させるタンパク質として同定したG0s2が生体内においても臓器保護的に作用することが示され、ATP産生増強による新規心不全治療法開発につながることが期待される。

Research Products

• [Journal Article] Detection of increased intracerebral lactate in a mouse model of Leigh syndrome using proton MR spectroscopy (2019)
  • Author(s): Takahashi Yusuke、Kioka Hidetaka、Shintani Yasunori、Ohki Akiko、Takashima Seiji、Sakata Yasushi、Higuchi Takahiro、Saito Shigeyoshi
  • Journal Title: Magnetic Resonance Imaging Volume: 58 Pages: 38-43
  • DOI: 10.1016/j.mri.2019.01.010
  • Peer Reviewed / Open Access
• [Journal Article] Non-Ischemic Heart Failure With Reduced Ejection Fraction Is Associated With Altered Intestinal Microbiota (2018)
  • Author(s): Katsimichas T, Ohtani T, Motooka D, Tsukamoto Y, Kioka H, Nakamoto K, Konishi S, Chimura M, Sengoku K, Miyawaki H, Sakaguchi T, Okumura R, Theofilis K, Iida T, Takeda K, Nakamura S, Sakata Y.
  • Journal Title: Circulation Journal Volume: 82 Issue: 6 Pages: 1640-1650
  • DOI: 10.1253/circj.CJ-17-1285
  • NAID: 130006744246
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2018-05-25
  • Peer Reviewed / Open Access
• [Journal Article] Successful treatment of severe combined post- and pre- capillary pulmonary hypertension in a patient with idiopathic restrictive cardiomyopathy. (2018)
  • Author(s): S. Ishihara, H. Kioka, T. Ohtani, Y. Asano, O. Yamaguchi, S. Hikoso, K. Toda, Y. Saito, Y. Sawa, K. Yamauchi-Takihara, Y. Sakata
  • Journal Title: Pulm Circ Volume: 8 Issue: 3 Pages: 1-5
  • DOI: 10.1177/2045894018770131
  • Peer Reviewed / Open Access
• [Journal Article] Liver Stiffness Reflecting Right-Sided Filling Pressure Can Predict Adverse Outcomes in Patients With Heart Failure. (2018)
  • Author(s): Taniguchi T, Ohtani T, Kioka H, Tsukamoto Y, Onishi T, Nakamoto K, Katsimichas T, Sengoku K, Chimura M, Hashimoto H, Yamaguchi O, Sawa Y, Sakata Y.
  • Journal Title: JACC Cardiovasc Imaging. Volume: - Issue: 6 Pages: 955-964
  • DOI: 10.1016/j.jcmg.2017.10.022
  • Peer Reviewed
• [Journal Article] Clinical Significance of Pulmonary Arterial Capacitance Calculated by Echocardiography in Patients With Advanced Heart Failure (2017)
  • Author(s): Saito Y, Ohtani T, Kioka H, Onishi T, Tsukamoto Y, Nakamoto K, Taniguchi T, Nakatani S, Hirayama A, Sakata Y.
  • Journal Title: Circulation Journal Volume: 81 Issue: 12 Pages: 1871-1878
  • DOI: 10.1253/circj.CJ-16-1318
  • NAID: 130006219112
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Cardiogenic shock caused by left mid-ventricular obstruction in a patient with anorexia nervosa; A novel cardiac manifestation of refeeding syndrome. (2017)
  • Author(s): Sakamoto Y, Kioka H, Hashimoto R, Takeda S, Ohtani T, Yamaguchi O, Wasa M, Nakatani S, Sakata Y.
  • Journal Title: Nutrition Volume: 35 Pages: 148-150
  • DOI: 10.1016/j.nut.2016.12.017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Interferon Therapy Exacerbated Pulmonary Hypertension in a Patient with Hepatitis C Virus Infection: Pathogenic Interplay among Multiple Risk Factors (2017)
  • Author(s): Tsuchiya H, Kioka H, Ozu K, Ohtani T, Yamaguchi O, Yazaki Y, Yamauchi-Takihara K, Sakata Y.
  • Journal Title: Internal Medicine Volume: 印刷中
  • NAID: 130005632048
• [Journal Article] <i>Capnocytophaga ochracea</i>-related Bacterium Bacteremia in a Hypertrophic Cardiomyopathy Patient without Neutropenia (2016)
  • Author(s): Capnocytophaga ochracea-related Bacterium Bacteremia in a Hypertrophic Cardiomyopathy Patient without Neutropenia.
  • Journal Title: Internal Medicine Volume: 55 Issue: 18 Pages: 2731-2735
  • DOI: 10.2169/internalmedicine.55.6593
  • NAID: 130005414816
  • ISSN: 0918-2918, 1349-7235
• [Journal Article] Btg2 is a Negative Regulator of Cardiomyocyte Hypertrophy through a Decrease in Cytosolic RNA. (2016)
  • Author(s): Masumura Y, Higo S, Asano Y, Kato H, Yan Y, Ishino S, Tsukamoto O, Kioka H, Hayashi T, Shintani Y, Yamazaki S, Minamino T, Kitakaze M, Komuro I, Takashima S, Sakata Y.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 28592-28592
  • DOI: 10.1038/srep28592
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] ”Analysis of genetic variants and chamber specific RNAexpressions in patients with advanced heart failure.” (2018)
  • Author(s): 木岡秀隆
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Onco-Pulmo Cardiology “Molecular Targeted Drugs Associate Pulmonary Vascular and Cardiac Diseases” (2018)
  • Author(s): 木岡秀隆
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Genetic Analysis and Chamber Specific Gene Expression Analysis in Patients with Cpc-PH and Ipc-PH (2018)
  • Author(s): Hidetaka Kioka
  • Organizer: The 6th World Symposium on Pulmonary Hypertension
  • Int'l Joint Research
• [Presentation] Mitochondrial Energy Metabolism and Potential Metabolic Therapy for Heart Failure (2016)
  • Author(s): 木岡 秀隆
  • Organizer: 第20回日本心不全学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-07
• [Remarks] 大阪大学大学院医学系研究科 循環器内科学 病態分子探索グループ
  • URL: http://www.cardiology.med.osaka-u.ac.jp/?page_id=56
• [Remarks] 大阪大学大学院医学系研究科 循環器内科学
  • URL: http://www.med.osaka-u.ac.jp/introduction/research/internal/cardiovascular
• [Remarks] 大阪大学大学院医学系研究科 医化学
  • URL: http://www.med.osaka-u.ac.jp/introduction/research/internal/cardiovascular