Impaired Myocardial Fatty Acid Oxidation and Reduced Protein Expression of Retinoid X Receptor-α in Pacing-Induced Heart Failure

Abstract

Background — The nuclear receptors peroxisome proliferator-activated receptor-α (PPARα) and retinoid X receptor α (RXRα) stimulate the expression of key enzymes of free fatty acid (FFA) oxidation. We tested the hypothesis that the altered metabolic phenotype of the failing heart involves changes in the protein expression of PPARα and RXRα. Methods and Results — Cardiac substrate uptake and oxidation were measured in 8 conscious, chronically instrumented dogs with decompensated pacing-induced heart failure and in 8 normal dogs by infusing 3 isotopically labeled substrates: 3 H-oleate, 14 C-glucose, and 13 C-lactate. Although myocardial O 2 consumption was not different between the 2 groups, the rate of oxidation of FFA was lower (2.8±0.6 versus 4.7±0.3 μmol · min −1 · 100g −1 ) and of glucose was higher (4.6±1.0 versus 1.8±0.5 μmol · min −1 · 100g −1 ) in failing compared with normal hearts ( P <0.05). The rates of lactate uptake and lactate output were not significantly different between the 2 groups. In left ventricular tissue from failing hearts, the activity of 2 key enzymes of FFA oxidation was significantly reduced: carnitine palmitoyl transferase-I (0.54±0.04 versus 0.66±0.04 μmol · min −1 · g −1 ) and medium chain acyl-coenzyme A dehydrogenase (MCAD; 1.8±0.1 versus 2.9±0.3 μmol · min −1 · g −1 ). Consistently, the protein expression of MCAD and of RXRα were significantly reduced by 38% in failing hearts, but the expression of PPARα was not different. Moreover, there were significant correlations between the expression of RXRα and the expression and activity of MCAD. Conclusions — Our results provide the first evidence for a link between the reduced expression of RXRα and the switch in metabolic phenotype in severe heart failure.