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On the pivotal role of PPARa in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury

Cole, Mark; Abd Jamil, Amira H.; Heather, Lisa C.; Murray, Andrew J.; Sutton, Elizabeth R.; Slingo, Mary; Sebag-Montefiore, Liam; Tan, Suat Cheng; Aksentijević, Dunja; Gildea, Ottilie S.; Stuckey, Daniel J.; Yeoh, Kar Kheng; Carr, Carolyn A.; Evans, Rhys D.; Aasum, Ellen; Schofield, Christopher J.; Ratcliffe, Peter J.; Neubauer, Stefan; Robbins, Peter A.; Clarke, Kieran

Authors

MARK COLE Mark.Cole@nottingham.ac.uk
Assistant Professor

Amira H. Abd Jamil

Lisa C. Heather

Andrew J. Murray

Elizabeth R. Sutton

Mary Slingo

Liam Sebag-Montefiore

Suat Cheng Tan

Dunja Aksentijević

Ottilie S. Gildea

Daniel J. Stuckey

Kar Kheng Yeoh

Carolyn A. Carr

Rhys D. Evans

Ellen Aasum

Christopher J. Schofield

Peter J. Ratcliffe

Stefan Neubauer

Peter A. Robbins

Kieran Clarke



Abstract

The role of peroxisome proliferator activated alpha (PPARα) -mediated metabolic remodeling in cardiac adaptation to hypoxia has yet to be defined. Here, mice were housed in hypoxia for 3 weeks before in vivo contractile function was measured using cine magnetic resonance (MR) imaging. In isolated, perfused hearts, energetics were measured using 31P MR spectroscopy and glycolysis and fatty acid oxidation were measured using 3H labelling. Compared with normoxic, chow-fed control mouse heart, hypoxia decreased PPARα expression, fatty acid oxidation and mitochondrial UCP3 levels, while increasing glycolysis, all of which served to maintain normal ATP concentrations 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 concentrations and contractile function decreased significantly. The adaptive metabolic changes caused by hypoxia in control mouse hearts were found to have already occurred in PPARα-/- mouse hearts, and sustained function in hypoxia despite an inability for further metabolic remodelling. We conclude that decreased cardiac PPARα expression is essential for adaptive metabolic remodelling in hypoxia, but is prevented by dietary fat.

Citation

Cole, M., Abd Jamil, A. H., Heather, L. C., Murray, A. J., Sutton, E. R., Slingo, M., …Clarke, K. (2016). On the pivotal role of PPARa in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury. FASEB Journal, 30(8), 2684-2697. https://doi.org/10.1096/fj.201500094R

Journal Article Type Article
Acceptance Date Apr 5, 2016
Online Publication Date Apr 21, 2016
Publication Date Aug 1, 2016
Deposit Date Jun 17, 2016
Publicly Available Date Jun 17, 2016
Journal FASEB Journal
Print ISSN 0892-6638
Electronic ISSN 0892-6638
Publisher Federation of American Society of Experimental Biology
Peer Reviewed Peer Reviewed
Volume 30
Issue 8
Pages 2684-2697
DOI https://doi.org/10.1096/fj.201500094R
Keywords Cardiac contractile function; Cine magnetic resonance imaging; Hypoxia inducible factor (HIF); Myocardial energy metabolism; 31 P Magnetic resonance spectroscopy; Substrate metabolism
Public URL http://eprints.nottingham.ac.uk/id/eprint/34100
Publisher URL http://www.fasebj.org/content/30/8/2684
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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