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Global metabolomic analysis of heart tissue in a hamster model for dilated cardiomyopathy
Keiko Maekawa1, Akiyoshi Hirayama, Yuko Iwata
1Project Team for Disease Metabolomics, National Institute of Health Sciences, Tokyo 158-8501, Japan.
Insights
Dilated cardiomyopathy involves metabolic disturbances, including altered phospholipid homeostasis and reduced energy production, leading to heart failure. These findings in a hamster model offer insights into disease mechanisms and potential therapeutic targets.
Area of Science:
- Cardiovascular Research
- Metabolomics
- Molecular Biology
Background:
- Dilated cardiomyopathy (DCM) is a major cause of heart failure with unclear underlying mechanisms.
- Understanding DCM pathogenesis is crucial for developing effective therapies and diagnostic tools.
Purpose of the Study:
- To investigate the mechanistic basis of DCM using a global metabolomic analysis.
- To identify metabolic alterations in the presymptomatic and symptomatic phases of DCM.
Main Methods:
- Global metabolomic analysis of left ventricular myocardial tissues from J2N-k cardiomyopathic hamsters and healthy controls.
- Measurement of charged and lipid metabolites using capillary electrophoresis mass spectrometry and liquid chromatography MS(/MS).
- Comparison of metabolite levels at presymptomatic (4 weeks) and symptomatic (16 weeks) stages.
Main Results:
- Early disturbances in membrane phospholipid homeostasis were observed in the presymptomatic phase.
- Symptomatic phase showed significant alterations in charged metabolites linked to glycolysis, pentose phosphate pathway, and TCA cycle, indicating reduced energy production.
- Increased oxidative stress markers (reduced glutathione, increased ophthalmate) and activated protective pathways (increased prostaglandins) were detected in diseased tissues.
Conclusions:
- Metabolic dysfunction, including impaired energy production and oxidative stress, contributes to DCM pathogenesis.
- The study provides mechanistic insights into DCM and suggests potential diagnostic and therapeutic targets.
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.
