Abstract |
Downregulation and functional deactivation of the transcriptional coactivator PGC-1alpha has been implicated in heart failure pathogenesis. We hypothesized that the estrogen-related receptor alpha ( ERRalpha), which recruits PGC-1alpha to metabolic target genes in heart, exerts protective effects in the context of stressors known to cause heart failure. ERRalpha(-/-) mice subjected to left ventricular (LV) pressure overload developed signatures of heart failure including chamber dilatation and reduced LV fractional shortening. (31)P-NMR studies revealed abnormal phosphocreatine depletion in ERRalpha(-/-) hearts subjected to hemodynamic stress, indicative of a defect in ATP reserve. Mitochondrial respiration studies demonstrated reduced maximal ATP synthesis rates in ERRalpha(-/-) hearts. Cardiac ERRalpha target genes involved in energy substrate oxidation, ATP synthesis, and phosphate transfer were downregulated in ERRalpha(-/-) mice at baseline or with pressure overload. These results demonstrate that the nuclear receptor ERRalpha is required for the adaptive bioenergetic response to hemodynamic stressors known to cause heart failure.
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Authors | Janice M Huss, Ken-ichi Imahashi, Catherine R Dufour, Carla J Weinheimer, Michael Courtois, Atilla Kovacs, Vincent Giguère, Elizabeth Murphy, Daniel P Kelly |
Journal | Cell metabolism
(Cell Metab)
Vol. 6
Issue 1
Pg. 25-37
(Jul 2007)
ISSN: 1550-4131 [Print] United States |
PMID | 17618854
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
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Chemical References |
- Biomarkers
- ERRalpha estrogen-related receptor
- RNA, Messenger
- Receptors, Estrogen
- Transcription Factors
- peroxisome-proliferator-activated receptor-gamma coactivator-1
- Adenosine Triphosphate
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Topics |
- Adaptation, Physiological
- Adenosine Triphosphate
(metabolism)
- Animals
- Animals, Newborn
- Biomarkers
(metabolism)
- Blood Pressure
- Cardiac Output, Low
- Cardiomegaly
(physiopathology)
- Energy Metabolism
- Female
- Gene Expression Profiling
- Heart
(embryology, physiopathology)
- Magnetic Resonance Spectroscopy
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Muscle Contraction
(physiology)
- Myocytes, Cardiac
(cytology, physiology)
- Oligonucleotide Array Sequence Analysis
- RNA, Messenger
(genetics, metabolism)
- Receptors, Estrogen
(physiology)
- Reverse Transcriptase Polymerase Chain Reaction
- Transcription Factors
(genetics, metabolism)
- Ventricular Pressure
(physiology)
- Ventricular Remodeling
(physiology)
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