On the pivotal role of PPARα in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury.
The role of peroxisome proliferator-activated receptor α (PPARα)-mediated metabolic remodeling in cardiac adaptation to hypoxia has yet to be defined. Here, mice were housed in hypoxia for 3 wk before in vivo contractile function was measured using cine MRI. In isolated, perfused hearts, energetics were measured using (31)P magnetic resonance spectroscopy (MRS), and glycolysis and fatty acid oxidation were measured using [(3)H] labeling. Compared with a normoxic, chow-fed control mouse heart, hypoxia decreased PPARα expression, fatty acid oxidation, and mitochondrial uncoupling protein 3 (UCP3) levels, while increasing glycolysis, all of which served to maintain normal ATP concentrations ([ATP]) and thereby, ejection fractions. A high-fat diet increased cardiac PPARα expression, fatty acid oxidation, and UCP3 levels with decreased glycolysis. Hypoxia was unable to alter the high PPARα expression or reverse the metabolic changes caused by the high-fat diet, with the result that [ATP] and contractile function decreased significantly. The adaptive metabolic changes caused by hypoxia in control mouse hearts were found to have occurred already in PPARα-deficient (PPARα(-/-)) mouse hearts and sustained function in hypoxia despite an inability for further metabolic remodeling. We conclude that decreased cardiac PPARα expression is essential for adaptive metabolic remodeling in hypoxia, but is prevented by dietary fat.-Cole, M. A., Abd Jamil, A. H., Heather, L. C., Murray, A. J., Sutton, E. R., Slingo, M., Sebag-Montefiore, L., Tan, S. C., Aksentijević, D., Gildea, O. S., Stuckey, D. J., Yeoh, K. K., Carr, C. A., Evans, R. D., Aasum, E., Schofield, C. J., Ratcliffe, P. J., Neubauer, S., Robbins, P. A., Clarke, K. On the pivotal role of PPARα in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury.
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;
Mark A
MA
Cole
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;
Amira H
AH
Abd Jamil
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;
Lisa C
LC
Heather
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;
Andrew J
AJ
Murray
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;
Elizabeth R
ER
Sutton
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;
Mary
M
Slingo
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom;
Liam
L
Sebag-Montefiore
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;
Suat Cheng
SC
Tan
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom;
Dunja
D
Aksentijević
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;
Ottilie S
OS
Gildea
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;
Daniel J
DJ
Stuckey
Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom; and.
Kar Kheng
KK
Yeoh
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;
Carolyn A
CA
Carr
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;
Rhys D
RD
Evans
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;
Ellen
E
Aasum
Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom; and.
Christopher J
CJ
Schofield
Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
Peter J
PJ
Ratcliffe
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom;
Stefan
S
Neubauer
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;
Peter A
PA
Robbins
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom; kieran.clarke@dpag.ox.ac.uk.
Kieran
K
Clarke
D000222:Adaptation, Physiological; D000821:Animal Feed / Q000032:analysis; D000818:Animals; D002460:Cell Line; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000502:physiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*
D004041:Dietary Fats; D047493:PPAR alpha
31P MRS; HIF; cardiac contractile function; myocardial energy metabolism; substrate metabolism