Development of in vivo four-dimensional [4D] metabolism imaging

• Project/Area Number: 19K17579
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Keio University
• Principal Investigator: KATSUMATA Yoshinori 慶應義塾大学, 医学部(信濃町), 講師 (80464832)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: メタボローム / 虚血再灌流 / 代謝 / マイクロダイアライシス / マイクロダイアラシス法 / 四次元代謝イメージング / 同位体元素 / グルタチオン / レドックス

Outline of Research at the Start

マイクロダイアラシス法を用いて、冠動脈結紮モデルにおける心筋局所の代謝の時間的変化を正確に把握することを目指す。このマイクロダイアラシスの技術と同位体元素を用いた定量的代謝フラックスイメージング（代謝の空間的把握）技術を組み合わせることで、in vivo 四次元代謝イメージング技術を確立する。そのうえで、このin vivo 四次元代謝イメージング技術を用いて、水素の同位体である重水素（2H2）の代謝動態を追跡し、水素の虚血再灌流障害抵抗性に関するメカニズムの解明を目指す。

Outline of Final Research Achievements

A microdialysis method was developed to capture the metabolic sequential changes during the hyperacute phase at the site of myocardial injury. A dialysate rope was implanted in the left ventricular myocardium of Wistar rats, perfused with an infusion pump, and the annulus fluid was collected from the tip for comprehensive analysis of metabolic products using mass spectrometry. The products were analyzed exhaustively by mass spectrometry. Significant variations in extracellular glutathione-related substances were revealed during ischemia and during reflux. In cultured cardiomyocytes, extracellular glutathione release increased during ischemia and reoxygenation, and intracellular reactive oxygen species and lipid peroxide increased over time. Intracellular glutathione levels were also maintained by glutathione administration, and cellular damage during ischemia and reoxygenation was suppressed.

Academic Significance and Societal Importance of the Research Achievements

虚血再灌流における詳細なRedox代謝変化を検証するため、空間的および時間的な網羅的代謝解析技術を確立した。マイクロ波による心臓処理を行うことで代謝産物の死後のdegradationを完全に抑制し、虚血再灌流時のRedox代謝産物の局在の可視化（マッピング）に成功した。さらに、虚血および再灌流に伴い、ダイナミックに変化する代謝産物の推移を時間軸で把握するために、メタボローム解析とマイクロダイアリシス法を組み合わせた、同一個体で心筋細胞外の代謝変化を連続的に測定する手法を確立した。これらの手法を組み合わせた代謝4次元マッピングは代謝物の時間的変化を明らかにした点に特色を有する。

Research Products

• [Journal Article] Qualitative and Quantitative Effects of Fatty Acids Involved in Heart Diseases (2022)
  • Author(s): Moriyama Hidenori、Endo Jin、Ikura Hidehiko、Kitakata Hiroki、Momoi Mizuki、Shinya Yoshiki、Ko Seien、Ichihara Genki、Hiraide Takahiro、Shirakawa Kohsuke、Anzai Atsushi、Katsumata Yoshinori、Sano Motoaki
  • Journal Title: Metabolites Volume: 12 Issue: 3 Pages: 210-210
  • DOI: 10.3390/metabo12030210
  • Peer Reviewed / Open Access
• [Journal Article] H2 Inhibits the Formation of Neutrophil Extracellular Traps. (2022)
  • Author(s): Kohsuke Shirakawa
  • Journal Title: JACC Basic Transl Sci. Volume: 7 Issue: 2 Pages: 146-161
  • DOI: 10.1016/j.jacbts.2021.11.005
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic Targets for DOX-Induced Cardiomyopathy: Role of Apoptosis vs. Ferroptosis (2022)
  • Author(s): Hiroki Kitakata, Jin Endo, Hidehiko Ikura, Hidenori Moriyama, Kohsuke Shirakawa, Yoshinori Katsumata, Motoaki Sano
  • Journal Title: International Journal of Molecular Sciences Volume: 23(3) Issue: 3 Pages: 1414-1414
  • DOI: 10.3390/ijms23031414
  • Peer Reviewed / Open Access
• [Journal Article] Time-Series Transcriptome Analysis Reveals the miR-27a-5p-<i>Ppm1l</i> Axis as a New Pathway Regulating Macrophage Alternative Polarization After Myocardial Infarction (2021)
  • Author(s): Shinichi Goto , Genki Ichihara , Yoshinori Katsumata , Seien Ko , Atsushi Anzai, Kohsuke Shirakawa, Jin Endo, Masaharu Kataoka , Hidenori Moriyama , Takahiro Hiraide, Hiroki Kitakata , Takayasu Kobayashi, Keiichi Fukuda , Motoaki Sano
  • Journal Title: Circulation Journal Volume: 85 Issue: 6 Pages: 929-938
  • DOI: 10.1253/circj.CJ-20-0783
  • NAID: 130008043200
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2021-05-25
  • Peer Reviewed / Open Access
• [Journal Article] Pharmacokinetics of hydrogen after ingesting a hydrogen-rich solution: A study in pigs (2021)
  • Author(s): Ichihara Genki、Katsumata Yoshinori、Moriyama Hidenori、Kitakata Hiroki、Hirai Akeo、Momoi Mizuki、Ko Seien、Shinya Yoshiki、Kinouchi Kenichiro、Kobayashi Eiji、Sano Motoaki
  • Journal Title: Heliyon Volume: 7 Issue: 11 Pages: e08359-e08359
  • DOI: 10.1016/j.heliyon.2021.e08359
  • Peer Reviewed / Open Access
• [Journal Article] MITOL/MARCH5 determines the susceptibility of cardiomyocytes to doxorubicin-induced ferroptosis by regulating GSH homeostasis (2021)
  • Author(s): Kitakata Hiroki、Endo Jin、Matsushima Hirokazu、Yamamoto Shoichi、Ikura Hidehiko、Hirai Akeo、Koh Seien、Ichihara Genki、Hiraide Takahiro、Moriyama Hidenori et al.
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 161 Pages: 116-129
  • DOI: 10.1016/j.yjmcc.2021.08.006
  • Peer Reviewed / Open Access
• [Journal Article] Imeglimin prevents heart failure with preserved ejection fraction by recovering the impaired unfolded protein response in mice subjected to cardiometabolic stress (2021)
  • Author(s): Kitakata Hiroki、Endo Jin、Hashimoto Shun、Mizuno Erika、Moriyama Hidenori、Shirakawa Kohsuke、Goto Shinichi、Katsumata Yoshinori、Fukuda Keiichi、Sano Motoaki
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 572 Pages: 185-190
  • DOI: 10.1016/j.bbrc.2021.07.090
  • Peer Reviewed / Open Access
• [Journal Article] <i>TNFRSF13B</i> c.226G>A (p.Gly76Ser) as a Novel Causative Mutation for Pulmonary Arterial Hypertension. (2021)
  • Author(s): Shinya Y, Hiraide T, Momoi M, Goto S, Suzuki H, Katsumata Y, Kurebayashi Y, Endo J, Sano M, Fukuda K, Kosaki K, Kataoka M.
  • Journal Title: J Am Heart Assoc. Volume: 10 Issue: 5
  • DOI: 10.1161/jaha.120.019245
  • Peer Reviewed / Open Access
• [Journal Article] A novel device for detecting anaerobic threshold using sweat lactate during exercise. (2021)
  • Author(s): Seki Y, Nakashima D, Shiraishi Y, Ryuzaki T, Ikura H, Miura K, Suzuki M, Watanabe T, Nagura T, Matsumato M, Nakamura M, Sato K, Fukuda K, Katsumata Y
  • Journal Title: Sci Rep. Volume: 2 Issue: 1 Pages: 4929-4929
  • DOI: 10.1038/s41598-021-84381-9
  • Peer Reviewed / Open Access
• [Journal Article] Daily inhalation of hydrogen gas has a blood pressure-lowering effect in a rat model of hypertension. (2020)
  • Author(s): 10: Sugai K, Tamura T, Sano M, Uemura S, Fujisawa M, Katsumata Y, Endo J, Yoshizawa J, Homma K, Suzuki M, Kobayashi E, Sasaki J, Hakamata Y.
  • Journal Title: Sci Rep. Volume: 10 Issue: 1
  • DOI: 10.1038/s41598-020-77349-8
  • Peer Reviewed
• [Journal Article] MerTK Expression and ERK Activation Are Essential for the Functional Maturation of Osteopontin-Producing Reparative Macrophages After Myocardial Infarction (2020)
  • Author(s): Kohsuke Shirakawa, Jin Endo , Masaharu Kataoka, Yoshinori Katsumata, Atsushi Anzai, Hidenori Moriyama, Hiroki Kitakata, Takahiro Hiraide, Seien Ko, Shinichi Goto, Genki Ichihara, Keiichi Fukuda, Tohru Minamino, Motoaki Sano
  • Journal Title: Journal of American Heart Association Volume: 9 Issue: 18
  • DOI: 10.1161/jaha.120.017071
  • Peer Reviewed / Open Access
• [Presentation] Quantitative measurement of the myocardial infarction area using Q-space magnetic resonance imaging (2022)
  • Author(s): Genki Ichihara, Junichi Hata, Daisuke Nakashima, Yawara Haga, Kyohei Daigo, Kazuhisa Sugai, Yuji Iwasawa, Yoshinori Katsumata, Jin Endo, Motoaki Sano, Eiji Kobayashi, Kazuki Sato, Masaya Nakamura, Keiichi Fukuda
  • Organizer: 第86回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] Continuous analysis of local in vivo metabolic changes using micro-dialysis technique (2021)
  • Author(s): Yohinori Katsumata, Genki Ichihara, Yuki Sugiura, Shinichi Goto, Seien Ko, Takahiro Hiraide, Hiroki Kitakata, Hidenori Moriyama, Kohsuke Shirakawa, Atsushi Anzai, Jin Endo, Masaharu Kataoka, Motoaki Sano, Keiichi Fukuda
  • Organizer: 第85回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] Continuous analysis of local in vivo metabolic changes using a microdialysis technique, (2021)
  • Author(s): Genki Ichihara, Yoshinori Katsumata, Yuki Sugiura, Shinichi Goto, Seien Ko, Takahiro Hiraide, Hiroki Kitakata, Hidenori Moriyama, Kohsuke Shirakawa, Atsushi Anzai, Jin Endo, Masaharu Kataoka, Motoaki Sano, Keiichi Fukuda,
  • Organizer: Japanese circulation Society
  • Int'l Joint Research
• [Presentation] Continuous analysis of local in vivo metabolic changes using a microdialysis technique, (2020)
  • Author(s): Yoshinori Katsumata, Genki Ichihara, Yuki Sugiura, Shinichi Goto, Seien Ko, Takahiro Hiraide, Hiroki Kitakata, Hidenori Moriyama, Kohsuke Shirakawa, Atsushi Anzai, Jin Endo, Masaharu Kataoka, Motoaki Sano, Keiichi Fukuda,
  • Organizer: The 4st JCS Council Forum on Basic Cardiovascular
  • Int'l Joint Research