The nuclear receptor ERRalpha is required for the bioenergetic and functional adaptation to cardiac pressure overload.

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.

• 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)

Chemical References

• Biomarkers
• ERRalpha estrogen-related receptor
• RNA, Messenger
• Receptors, Estrogen
• Transcription Factors
• peroxisome-proliferator-activated receptor-gamma coactivator-1
• Adenosine Triphosphate

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)