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


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.


Cardiac metabolism Metabolomics Pyruvate dehydrogenase Glycolysis Monocrotaline 



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)


  1. 1.
    Ashrafian H, Frenneaux MP, Opie LH (2007) Metabolic mechanisms in heart failure. Circulation 116:434–448CrossRefGoogle Scholar
  2. 2.
    Doenst T, Nguyen TD, Abel ED (2013) Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res 113:709–724CrossRefGoogle Scholar
  3. 3.
    Lopaschuk GD, Jaswal JS (2010) Energy metabolic phenotype of the cardiomyocyte during development, differentiation, and postnatal maturation. J Cardiovasc Pharmacol 56:130–140CrossRefGoogle Scholar
  4. 4.
    Varga ZV, Ferdinandy P, Liaudet L, Pacher P (2015) Drug-induced mitochondrial dysfunction and cardiotoxicity. Am J Physiol Heart Circ Physiol 309:H1453–H1467CrossRefGoogle Scholar
  5. 5.
    Stanley WC, Recchia FA, Lopaschuk GD (2005) Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 85:1093–1129CrossRefGoogle Scholar
  6. 6.
    Ventura-Clapier R, Garnier A, Veksler V (2004) Energy metabolism in heart failure. J Physiol 555:1–13CrossRefGoogle Scholar
  7. 7.
    Shimura D, Nakai G, Jiao Q, Osanai K, Kashikura K, Endo K, Soga T, Goda N, Minamisawa S (2013) Metabolomic profiling analysis reveals chamber-dependent metabolite patterns in the mouse heart. Am J Physiol Heart Circ Physiol 305:H494–H505CrossRefGoogle Scholar
  8. 8.
    Piao L, Fang YH, Cadete VJ, Wietholt C, Urboniene D, Toth PT, Marsboom G, Zhang HJ, Haber I, Rehman J, Lopaschuk GD, Archer SL (2010) The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle. J Mol Med (Berl) 88:47–60CrossRefGoogle Scholar
  9. 9.
    Daicho T, Yagi T, Abe Y, Ohara M, Marunouchi T, Takeo S, Tanonaka K (2009) Possible involvement of mitochondrial energy-producing ability in the development of right ventricular failure in monocrotaline-induced pulmonary hypertensive rats. J Pharmacol Sci 111:33–43CrossRefGoogle Scholar
  10. 10.
    Kumar S, Wei C, Thomas CM, Kim IK, Seqqat R, Kumar R, Baker KM, Jones WK, Gupta S (2012) Cardiac-specific genetic inhibition of nuclear factor-kappaB prevents right ventricular hypertrophy induced by monocrotaline. Am J Physiol Heart Circ Physiol 302:H1655–H1666CrossRefGoogle Scholar
  11. 11.
    George J, D'Armiento J (2011) Transgenic expression of human matrix metalloproteinase-9 augments monocrotaline-induced pulmonary arterial hypertension in mice. J Hypertens 29:299–308CrossRefGoogle Scholar
  12. 12.
    Winter CK, Segall HJ, Jones AD (1988) Determination of pyrrolizidine alkaloid metabolites from mouse liver microsomes using tandem mass spectrometry and gas chromatography/mass spectrometry. Biomed Environ Mass Spectrom 15:265–273CrossRefGoogle Scholar
  13. 13.
    Gomez-Arroyo JG, Farkas L, Alhussaini AA, Farkas D, Kraskauskas D, Voelkel NF, Bogaard HJ (2012) The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Lung Cell Mol Physiol 302:L363–L369CrossRefGoogle Scholar
  14. 14.
    Gomez-Arroyo J, Saleem SJ, Mizuno S, Syed AA, Bogaard HJ, Abbate A, Taraseviciene-Stewart L, Sung Y, Kraskauskas D, Farkas D, Conrad DH, Nicolls MR, Voelkel NF (2012) A brief overview of mouse models of pulmonary arterial hypertension: problems and prospects. Am J Physiol Lung Cell Mol Physiol 302:L977–L991CrossRefGoogle Scholar
  15. 15.
    Soga T, Baran R, Suematsu M, Ueno Y, Ikeda S, Sakurakawa T, Kakazu Y, Ishikawa T, Robert M, Nishioka T, Tomita M (2006) Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption. J Biol Chem 281:16768–16776CrossRefGoogle Scholar
  16. 16.
    Soga T, Ohashi Y, Ueno Y, Naraoka H, Tomita M, Nishioka T (2003) Quantitative metabolome analysis using capillary electrophoresis mass spectrometry. J Proteome Res 2:488–494CrossRefGoogle Scholar
  17. 17.
    Jiao Q, Bai Y, Akaike T, Takeshima H, Ishikawa Y, Minamisawa S (2009) Sarcalumenin is essential for maintaining cardiac function during endurance exercise training. Am J Physiol Heart Circ Physiol 297:H576–H582CrossRefGoogle Scholar
  18. 18.
    Petry TW, Bowden GT, Huxtable RJ, Sipes IG (1984) Characterization of hepatic DNA damage induced in rats by the pyrrolizidine alkaloid monocrotaline. Cancer Res 44:1505–1509Google Scholar
  19. 19.
    Ezzat T, van den Broek MA, Davies N, Dejong CH, Bast A, Malago M, Dhar DK, Olde Damink SW (2012) The flavonoid monoHER prevents monocrotaline-induced hepatic sinusoidal injury in rats. J Surg Oncol 106:72–78CrossRefGoogle Scholar
  20. 20.
    Copple BL, Rondelli CM, Maddox JF, Hoglen NC, Ganey PE, Roth RA (2004) Modes of cell death in rat liver after monocrotaline exposure. Toxicol Sci 77:172–182CrossRefGoogle Scholar
  21. 21.
    Akhavein F, St-Michel EJ, Seifert E, Rohlicek CV (2007) Decreased left ventricular function, myocarditis, and coronary arteriolar medial thickening following monocrotaline administration in adult rats. J Appl Physiol (1985) 103:287–295CrossRefGoogle Scholar
  22. 22.
    Mori J, Basu R, McLean BA, Das SK, Zhang L, Patel VB, Wagg CS, Kassiri Z, Lopaschuk GD, Oudit GY (2012) Agonist-induced hypertrophy and diastolic dysfunction are associated with selective reduction in glucose oxidation: a metabolic contribution to heart failure with normal ejection fraction. Circ Heart Fail 5:493–503CrossRefGoogle Scholar
  23. 23.
    Atherton HJ, Dodd MS, Heather LC, Schroeder MA, Griffin JL, Radda GK, Clarke K, Tyler DJ (2011) Role of pyruvate dehydrogenase inhibition in the development of hypertrophy in the hyperthyroid rat heart: a combined magnetic resonance imaging and hyperpolarized magnetic resonance spectroscopy study. Circulation 123:2552–2561CrossRefGoogle Scholar
  24. 24.
    Rich S (2012) Right ventricular adaptation and maladaptation in chronic pulmonary arterial hypertension. Cardiol Clin 30:257–269CrossRefGoogle Scholar
  25. 25.
    Fillmore N, Lopaschuk GD (2013) Targeting mitochondrial oxidative metabolism as an approach to treat heart failure. Biochim Biophys Acta 1833:857–865CrossRefGoogle Scholar
  26. 26.
    Ussher JR, Jaswal JS, Lopaschuk GD (2012) Pyridine nucleotide regulation of cardiac intermediary metabolism. Circ Res 111:628–641CrossRefGoogle Scholar
  27. 27.
    Sabbah HN, Chandler MP, Mishima T, Suzuki G, Chaudhry P, Nass O, Biesiadecki BJ, Blackburn B, Wolff A, Stanley WC (2002) Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, improves left ventricular function in dogs with chronic heart failure. J Card Fail 8:416–422CrossRefGoogle Scholar
  28. 28.
    Fang YH, Piao L, Hong Z, Toth PT, Marsboom G, Bache-Wiig P, Rehman J, Archer SL (2012) Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: exploiting Randle's cycle. J Mol Med (Berl) 90:31–43CrossRefGoogle Scholar
  29. 29.
    Lionetti V, Linke A, Chandler MP, Young ME, Penn MS, Gupte S, d'Agostino C, Hintze TH, Stanley WC, Recchia FA (2005) Carnitine palmitoyl transferase-I inhibition prevents ventricular remodeling and delays decompensation in pacing-induced heart failure. Cardiovasc Res 66:454–461CrossRefGoogle Scholar
  30. 30.
    Chandler MP, Chavez PN, McElfresh TA, Huang H, Harmon CS, Stanley WC (2003) Partial inhibition of fatty acid oxidation increases regional contractile power and efficiency during demand-induced ischemia. Cardiovasc Res 59:143–151CrossRefGoogle Scholar

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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