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Heart and Vessels

, Volume 34, Issue 3, pp 545–555 | Cite as

Pyruvate dehydrogenase activation precedes the down-regulation of fatty acid oxidation in monocrotaline-induced myocardial toxicity in mice

  • Gaku Nakai
  • Daisuke Shimura
  • Ken Uesugi
  • Ichige Kajimura
  • Qibin Jiao
  • Yoichiro Kusakari
  • Tomoyoshi Soga
  • Nobuhito Goda
  • Susumu MinamisawaEmail author
Original Article

Abstract

Fatty acid (FA) oxidation is impaired and glycolysis is promoted in the damaged heart. However, the factor(s) in the early stages of myocardial metabolic impairment remain(s) unclear. C57B6 mice were subcutaneously administered monocrotaline (MCT) in doses of 0.3 mg/g body weight twice a week for 3 or 6 weeks. Right and left ventricles at 3 and 6 weeks after administration were subjected to capillary electrophoresis–mass spectrometry metabolomic analysis. We also examined mRNA and protein levels of key metabolic molecules. Although no evidence of PH and right ventricular failure was found in the MCT-administered mice by echocardiographic and histological analyzes, the expression levels of stress markers such as TNFα and IL-6 were increased in right and left ventricles even at 3 weeks, suggesting that there was myocardial damage. Metabolites in the tricarboxylic acid (TCA) cycle were decreased and those in glycolysis were increased at 6 weeks. The expression levels of FA oxidation-related factors were decreased at 6 weeks. The phosphorylation level of pyruvate dehydrogenase (PDH) was significantly decreased at 3 weeks. FA oxidation and the TCA cycle were down-regulated, whereas glycolysis was partially up-regulated by MCT-induced myocardial damage. PDH activation preceded these alterations, suggesting that PDH activation is one of the earliest events to compensate for a subtle metabolic impairment from myocardial damage.

Keywords

Cardiac metabolism Metabolomics Pyruvate dehydrogenase Glycolysis Monocrotaline 

Notes

Acknowledgements

This work was supported by Grants from the Ministry of Health, Labor and Welfare of Japan (S.M.), the Ministry of Education, Culture, Sports, Science and Technology of Japan (S.M.), the “High-Tech Research Center” Project for Private Universities: MEXT (N.G., S.M.), the Vehicle Racing Commemorative Foundation (S.M.), and Takatomi Research Promotion Funds (Q.J.).

Author contributions

SM and NG conceived and designed the experiments; GN, DS, and KU performed the experiments; GN, DS, and TS analyzed the data; IK and QJ contributed reagents/materials/analysis tools; GN, DS, and SM wrote the paper.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

380_2018_1293_MOESM1_ESM.jpg (25 kb)
Supplemental figure 1. The expression levels of CD163 were significantly increased in the RV of 3-week and the LV of 6-week MCT-administered mice. n = 3 ~ 6 in each group except RV at 6-week control mice. Only one sample was available for the RV at 6-week control mice. 18s rRNA was used as an internal control. Values are expressed as mean ± SEM. Abbreviations: RV, right ventricle; LV, left ventricle; 3w, 3-week administration; 6w, 6-week administration. *P < 0.05 compared to control group (JPG 25 kb)
380_2018_1293_MOESM2_ESM.jpg (27 kb)
Supplemental figure 2. Body weight of the MCT-administered mice was lower than that of the control group from around 3 weeks of administration. Values are expressed as mean ± SEM. n = 12 ~ 13 in each group. ***P < 0.001 compared to control group (JPG 27 kb)

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Copyright information

© Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Life Science and Medical BioscienceWaseda UniversityTokyoJapan
  2. 2.Department of Cell PhysiologyThe Jikei University School of MedicineTokyoJapan
  3. 3.Department of CardiologyThe Affiliated Hospital of Hangzhou Normal UniversityHangzhouChina
  4. 4.Institute for Advanced BiosciencesKeio UniversityYamagataJapan

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