Global metabolomic analysis of heart tissue in a hamster model for dilated cardiomyopathy

Keiko Maekawa, Akiyoshi Hirayama, Yuko Iwata, Yoko Tajima, Tomoko Nishimaki-Mogami, Shoko Sugawara, Noriko Ueno, Hiroshi Abe, Masaki Ishikawa, Mayumi Murayama, Yumiko Matsuzawa, Hiroki Nakanishi, Kazutaka Ikeda, Makoto Arita, Ryo Taguchi, Naoto Minamino, Shigeo Wakabayashi, Tomoyoshi Soga, Yoshiro Saito

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

Dilated cardiomyopathy (DCM), a common cause of heart failure, is characterized by cardiac dilation and reduced left ventricular ejection fraction, but the underlying mechanisms remain unclear. To investigate the mechanistic basis, we performed global metabolomic analysis of myocardial tissues from the left ventricles of J2N-k cardiomyopathic hamsters. This model exhibits symptoms similar to those of human DCM, owing to the deletion of the δ-sarcoglycan gene. Charged and lipid metabolites were measured by capillary electrophoresis mass spectrometry (MS) and liquid chromatography MS(/MS), respectively, and J2N-k hamsters were compared with J2N-n healthy controls at 4 (presymptomatic phase) and 16 weeks (symptomatic) of age. Disturbances in membrane phospholipid homeostasis were initiated during the presymptomatic phase. Significantly different levels of charged metabolites, occurring mainly in the symptomatic phase, were mapped to primary metabolic pathways. Reduced levels of metabolites in glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle, together with large decreases in major triacylglycerol levels, suggested that decreased energy production leads to cardiac contractile dysfunction in the symptomatic phase. A mild reduction in glutathione and a compensatory increase in ophthalmate levels suggest increased oxidative stress in diseased tissues, which was confirmed by histochemical staining. Increased levels of 4 eicosanoids, including prostaglandin (PG) E2 and 6-keto-PGF, in the symptomatic phase suggested activation of the protective response pathways. These results provide mechanistic insights into DCM pathogenesis and may help identify new targets for therapeutic intervention and diagnosis.

Original languageEnglish
Pages (from-to)76-85
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume59
DOIs
Publication statusPublished - 2013 Jun 1

Keywords

  • Dilated cardiomyopathy
  • Hamster model
  • Metabolomics
  • Oxidative stress
  • Phospholipid alteration

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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