FATTY-ACID OXIDATION ENZYME GENE-EXPRESSION IS DOWN-REGULATED IN THE FAILING HEART

Background During the development of heart failure (HF), the chief myo cardial energy substrate switches from fatty acids to glucose. This me tabolic switch, which recapitulates fetal cardiac energy substrate pre ferences, is thought to maintain aerobic energetic balance. The regula tory mechanisms involved in this metabolic response are unknown. Metho ds and Results To characterize the expression of genes involved in mit ochondrial fatty acid beta-oxidation (FAG) in the failing heart, level s of mRNA encoding enzymes that catalyze the first and third steps of the FAO cycle were delineated in the left ventricles (LVs) of human ca rdiac transplant recipients. FAO enzyme and mRNA levels were coordinat ely downregulated (>40%) in failing human LVs compared with controls. The temporal pattern of this alteration in FAO enzyme gene expression was characterized in a rat model of progressive LV hypertrophy (LVH) a nd HF [SHHF/Mcc-fa(cp) (SHHF) rat]. FAO enzyme mRNA levels were coordi nately downregulated (>70%) during both the LVH and HF stages in the S HHF rats compared with controls. In contrast, the activity and steady- state levels of medium-chain acyl-CoA dehydrogenase, which catalyzes a rate-limiting step in FAG, were not significantly reduced until the H F stage, indicating additional control at the translational or posttra nslational levels in the hypertrophied but nonfailing ventricle. Concl usions These findings identify a gene regulatory pathway involved in t he control of cardiac energy production during the development of HF.