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01.11.2018 | Original Article | Ausgabe 3/2019

Heart and Vessels 3/2019

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

Zeitschrift:
Heart and Vessels > Ausgabe 3/2019
Autoren:
Gaku Nakai, Daisuke Shimura, Ken Uesugi, Ichige Kajimura, Qibin Jiao, Yoichiro Kusakari, Tomoyoshi Soga, Nobuhito Goda, Susumu Minamisawa
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s00380-018-1293-3) contains supplementary material, which is available to authorized users.

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.

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Zusatzmaterial
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_MOESM1_ESM.jpg
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)
380_2018_1293_MOESM2_ESM.jpg
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