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

Abstract

The role of peroxisome proliferator-activated receptor a (PPARa)-mediated metabolic remodeling in cardiac adaptation tohypoxia has yet to be defined.Here,micewere housed inhypoxia for 3wkbefore in vivo contractile function was measured using cine MRI. In isolated, perfused hearts, energetics were measured using 31P magnetic resonance spectroscopy (MRS), and glycolysis and fatty acid oxidation were measured using [3H] labeling. Compared with a normoxic, chow-fed control mouse heart, hypoxia decreased PPARa expression, fatty acid oxidation, and mitochondrial uncouplingprotein3(UCP3)levels,whileincreasing glycolysis,allofwhichservedtomaintainnormalATPconcentrations ([ATP]) andthereby, ejection fractions.Ahigh-fatdiet increased cardiacPPARa expression, fatty acid oxidation,andUCP3 levels with decreased glycolysis.Hypoxiawasunable to alter the highPPARa 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 PPARa-deficient (PPARa2/2) mouse hearts and sustained function in hypoxia despite an inability for further metabolic remodeling. We conclude that decreased cardiac PPARa 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., Aksentijevíc,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 PPARa in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury.