Peroxisome proliferator-activated receptor alpha is downregulated in the failing human heart.

Cardiac hypertrophy in humans is associated with a decrease in myocardial fatty acid beta-oxidation (FAO) and accompanying alterations in metabolic gene expression. Flux through the cardiac FAO pathway, which is the principal source of energy production in the adult mammalian heart, is tightly controlled in accordance with energy demands. In rodents, the FAO pathway is under control of a nuclear peroxisome proliferator-activated receptor alpha (PPARalpha?. We sought to delineate the molecular regulatory events involved in the energy substrate preference switch from fatty acids to glucose during cardiac hypertrophic growth in humans. We analysed the amount of PPARalpha protein in human cardiac tissue. PPARalpha protein level was measured in homogenates prepared from left ventricular biopsies taken from five control donor hearts and compared to the amount of this transcription factor in biopsies from five patients with compensated end-stage heart failure (HF) at the time of transplantation. Using Western blot analysis with a monoclonal antibody against human PPARalpha, we observed a significant decrease (54%) in the mean amount of PPARalpha in the group of HF patients compared to that in the donor tissue. This study indicates that the decrease in cardiac PPARalpha transcription factor gene expression observed in the failing human heart could play an important role in a reduction in fatty acid utilisation by the adult heart during cardiac hypertrophy.