The nuclear receptor ERRalpha is required for the bioenergetic and functional adaptation to cardiac pressure overload.
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.
Huss
Janice M
JM
Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
Imahashi
Ken-ichi
K
Dufour
Catherine R
CR
Weinheimer
Carla J
CJ
Courtois
Michael
M
Kovacs
Atilla
A
Giguère
Vincent
V
Murphy
Elizabeth
E
Kelly
Daniel P
DP
D000222:Adaptation, Physiological; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure; D002303:Cardiac Output, Low; D006332:Cardiomegaly / Q000503:physiopathology; D004734:Energy Metabolism; D005260:Female; D020869:Gene Expression Profiling; D006321:Heart / Q000196:embryology / Q000503:physiopathology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D017725:Ventricular Pressure / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*; D000097983:ERRalpha Estrogen-Related Receptor
D000255:Adenosine Triphosphate; D015415:Biomarkers; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1