Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-α in pacing-induced heart failure

Background-The nuclear receptors peroxisome proliferator-activated receptor-alpha (PPARalpha) and retinoid X receptor alpha (RYRalpha) 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 PPARalpha and RXRalpha. 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: H-3-oleate,C-14-glucose, and C-13-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 mumol.min(-1).100g(-1)) and of glucose was higher (4.6+/-1.0 versus 1.8+/-0.5mumol.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 mumol.min(-1).g(-1)) and medium chain acyl-coenzyme A dehydrogenase (MCAD; 1.8+/-0.1 versus 2.9+/-0.3 mumol.min(-1).g(-1)). Consistently, the protein expression of MCAD and of RXRalpha were significantly reduced by 38% in failing hearts, but the expression of PPARalpha was not different. Moreover, there were significant correlations between the expression of RXRalpha and the expression and activity of MCAD. Conclusions-Our results provide the first evidence for a link between the reduced expression of RXRalpha and the switch in metabolic phenotype in severe heart failure.