Fatty Acid Oxidation Enzyme Gene Expression Is Downregulated in the Failing Heart

TLDR

Heart failure is accompanied by a metabolic shift from fatty acids to glucose, a fetal-like substrate preference that is thought to preserve aerobic energy balance. The study aimed to uncover the regulatory mechanisms driving this metabolic response. Researchers quantified mRNA levels of key fatty‑acid β‑oxidation enzymes in human failing hearts and monitored their temporal expression in a rat model of progressive LV hypertrophy and heart failure. FAO enzyme mRNA was coordinately downregulated by >40 % in human hearts and >70 % in the rat model, yet enzyme activity remained unchanged until the heart‑failure stage, indicating a gene‑regulatory pathway that controls cardiac energy production during disease progression.

Abstract

Background During the development of heart failure (HF), the chief myocardial energy substrate switches from fatty acids to glucose. This metabolic switch, which recapitulates fetal cardiac energy substrate preferences, is thought to maintain aerobic energetic balance. The regulatory mechanisms involved in this metabolic response are unknown. Methods and Results To characterize the expression of genes involved in mitochondrial fatty acid β-oxidation (FAO) in the failing heart, levels of mRNA encoding enzymes that catalyze the first and third steps of the FAO cycle were delineated in the left ventricles (LVs) of human cardiac transplant recipients. FAO enzyme and mRNA levels were coordinately 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) and HF [SHHF/Mcc- fa cp (SHHF) rat]. FAO enzyme mRNA levels were coordinately downregulated (>70%) during both the LVH and HF stages in the SHHF 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 FAO, were not significantly reduced until the HF stage, indicating additional control at the translational or posttranslational levels in the hypertrophied but nonfailing ventricle. Conclusions These findings identify a gene regulatory pathway involved in the control of cardiac energy production during the development of HF.