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 alpha (PPAR alpha)-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 P-31 magnetic resonance spectroscopy (MRS), and glycolysis and fatty acid oxidation were measured using [H-3] labeling. Compared with a nor-moxic, chow-fed control mouse heart, hypoxia decreased PPAR alpha expression, fatty acid oxidation, and mitochondrial uncouplingprotein 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 PPAR alpha expression, fatty acid oxidation, and UCP3 levels with decreased glycolysis. Hypoxia was unable to alter the high PPAR alpha 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 PPAR alpha-deficient (PPAR alpha(-/-)) mouse hearts and sustained function in hypoxia despite an inability for further metabolic remodeling. We conclude that decreased cardiac PPAR alpha expression is essential for adaptive metabolic remodeling in hypoxia, but is prevented by dietary fat.