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Energy metabolic reprogramming in the hypertrophied and early stage failing heart: a multisystems approach.

Publication ,  Journal Article
Lai, L; Leone, TC; Keller, MP; Martin, OJ; Broman, AT; Nigro, J; Kapoor, K; Koves, TR; Stevens, R; Ilkayeva, OR; Vega, RB; Attie, AD ...
Published in: Circ Heart Fail
November 2014

BACKGROUND: An unbiased systems approach was used to define energy metabolic events that occur during the pathological cardiac remodeling en route to heart failure (HF). METHODS AND RESULTS: Combined myocardial transcriptomic and metabolomic profiling were conducted in a well-defined mouse model of HF that allows comparative assessment of compensated and decompensated (HF) forms of cardiac hypertrophy because of pressure overload. The pressure overload data sets were also compared with the myocardial transcriptome and metabolome for an adaptive (physiological) form of cardiac hypertrophy because of endurance exercise training. Comparative analysis of the data sets led to the following conclusions: (1) expression of most genes involved in mitochondrial energy transduction were not significantly changed in the hypertrophied or failing heart, with the notable exception of a progressive downregulation of transcripts encoding proteins and enzymes involved in myocyte fatty acid transport and oxidation during the development of HF; (2) tissue metabolite profiles were more broadly regulated than corresponding metabolic gene regulatory changes, suggesting significant regulation at the post-transcriptional level; (3) metabolomic signatures distinguished pathological and physiological forms of cardiac hypertrophy and served as robust markers for the onset of HF; and (4) the pattern of metabolite derangements in the failing heart suggests bottlenecks of carbon substrate flux into the Krebs cycle. CONCLUSIONS: Mitochondrial energy metabolic derangements that occur during the early development of pressure overload-induced HF involve both transcriptional and post-transcriptional events. A subset of the myocardial metabolomic profile robustly distinguished pathological and physiological cardiac remodeling.

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Published In

Circ Heart Fail

DOI

EISSN

1941-3297

Publication Date

November 2014

Volume

7

Issue

6

Start / End Page

1022 / 1031

Location

United States

Related Subject Headings

  • Ventricular Remodeling
  • Up-Regulation
  • Mice
  • Metabolome
  • Lipid Metabolism
  • Heart Failure
  • Gene Expression Profiling
  • Energy Metabolism
  • Down-Regulation
  • Disease Models, Animal
 

Citation

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Lai, L., Leone, T. C., Keller, M. P., Martin, O. J., Broman, A. T., Nigro, J., … Kelly, D. P. (2014). Energy metabolic reprogramming in the hypertrophied and early stage failing heart: a multisystems approach. Circ Heart Fail, 7(6), 1022–1031. https://doi.org/10.1161/CIRCHEARTFAILURE.114.001469

Published In

Circ Heart Fail

DOI

EISSN

1941-3297

Publication Date

November 2014

Volume

7

Issue

6

Start / End Page

1022 / 1031

Location

United States

Related Subject Headings

  • Ventricular Remodeling
  • Up-Regulation
  • Mice
  • Metabolome
  • Lipid Metabolism
  • Heart Failure
  • Gene Expression Profiling
  • Energy Metabolism
  • Down-Regulation
  • Disease Models, Animal