The energy substrate switch during development of heart failure: gene regulatory mechanisms (Review).
During cardiac hypertrophy and in the failing heart, the chief myocardial energy substrate switches from fatty acids to glucose. In this review, we describe recent progress in the elucidation of the molecular regulatory events involved in the dramatic downregulation of the expression of fatty acid utilization enzymes during development of cardiac hypertrophy and failure. Much of this work has focused on the gene encoding medium-chain acyl-CoA dehydrogenase (MCAD), which catalyzes a pivotal step in the mitochondrial fatty acid -oxidation (FAO) cycle. In vivo ventricular pressure overload studies performed in mice transgenic for human MCAD promoter fragments linked to reporter genes have shown that transcription is markedly downregulated within seven days of pressure overload. The temporal pattern of this alteration in MCAD gene expression has also been characterized in a rat model of progressive pressure overload-induced left ventricular hypertrophy (LVH) and heart failure (HF) [SHHF/Mcc-facp (SHHF) rat]. MCAD mRNA levels are downregulated (>70%) during both the LVH and HF stages in the SHHF rats compared with controls. In contrast, the activity and immunodetectable levels of MCAD enzyme were not significantly reduced until the HF stage, indicating additional compensatory control at the translational or post-translational levels in the hypertrophied but non-failing ventricle. FAO enzyme expression was also shown to be downregulated in human subjects with dilated cardiomyopathy compared to age-matched controls. Taken together, these results have identified a gene regulatory program that is involved in the alterations in myocardial energy substrate utilization in the failing heart. The temporal correlation of diminished enzyme expression with onset of heart failure suggests that this alteration in lipid metabolism may play a role in the pathogenesis of pressure-overload induced heart failure. This gene regulatory pathway should be a useful target for experimental studies aimed at the molecular pathogenesis of the transition from stable cardiac hypertrophy to overt heart failure.
Sack
M N
MN
Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Kelly
D P
DP
D042964:Acyl-CoA Dehydrogenase; D044944:Acyl-CoA Dehydrogenases / Q000235:genetics*; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000503:physiopathology; D009202:Cardiomyopathies / Q000201:enzymology; D018450:Disease Progression; D004735:Energy Transfer; D005227:Fatty Acids / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D051379:Mice; D012323:RNA Processing, Post-Transcriptional; D051381:Rats; D014158:Transcription, Genetic
D005227:Fatty Acids; D044944:Acyl-CoA Dehydrogenases; D042964:Acyl-CoA Dehydrogenase