title: Global metabolomic analysis of heart tissue in a hamster model for dilated cardiomyopathy.
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 16weeks (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-PGF1α, 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.
authors: Project Team for Disease Metabolomics, National Institute of Health Sciences, Tokyo 158-8501, Japan.
authors: Keiko
authors: K
authors: Maekawa
authors: Akiyoshi
authors: A
authors: Hirayama
authors: Yuko
authors: Y
authors: Iwata
authors: Yoko
authors: Y
authors: Tajima
authors: Tomoko
authors: T
authors: Nishimaki-Mogami
authors: Shoko
authors: S
authors: Sugawara
authors: Noriko
authors: N
authors: Ueno
authors: Hiroshi
authors: H
authors: Abe
authors: Masaki
authors: M
authors: Ishikawa
authors: Mayumi
authors: M
authors: Murayama
authors: Yumiko
authors: Y
authors: Matsuzawa
authors: Hiroki
authors: H
authors: Nakanishi
authors: Kazutaka
authors: K
authors: Ikeda
authors: Makoto
authors: M
authors: Arita
authors: Ryo
authors: R
authors: Taguchi
authors: Naoto
authors: N
authors: Minamino
authors: Shigeo
authors: S
authors: Wakabayashi
authors: Tomoyoshi
authors: T
authors: Soga
authors: Yoshiro
authors: Y
authors: Saito
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000378:metabolism*; D002853:Chromatography, Liquid; D006224:Cricetinae; D004195:Disease Models, Animal; D019075:Electrophoresis, Capillary; D013058:Mass Spectrometry; D055432:Metabolomics / Q000379:methods*; D018384:Oxidative Stress / Q000502:physiology; D010743:Phospholipids / Q000378:metabolism
chemical_list: D010743:Phospholipids