THE ENERGY SUBSTRATE SWITCH DURING DEVELOPMENT OF HEART-FAILURE - GENE REGULATORY MECHANISMS (REVIEW)

During cardiac hypertrophy and in the failing heart, the chief myocard ial energy substrate switches from fatty acids to glucose. In this rev iew, we describe recent progress in the elucidation of the molecular r egulatory events involved in the dramatic downregulation of the expres sion of fatty acid utilization enzymes during development of cardiac h ypertrophy and failure. Much of this work has focused on the gene enco ding medium-chain acyl-CoA dehydrogenase (MCAD), which catalyzes a piv otal step in the mitochondrial fatty acid beta-oxidation (FAO) cycle. In vivo ventricular pressure overload studies performed in mice transg enic for human MCAD promoter fragments linked to reporter genes have s hown that transcription is markedly downregulated within seven days of pressure overload. The temporal pattern of this alteration in MCAD ge ne expression has also been characterized in a rat model of progressiv e pressure overload-induced left ventricular hypertrophy (LVH) and hea rt failure (HF) [SHHF/Mcc-fa(cp) (SHHF) rat]. MCAD mRNA levels are dow nregulated (>70%) during both the LVH and HF stages in the SHHF rats c ompared with controls. In contrast, the activity and immunodetectable levels of MCAD enzyme were not significantly reduced until the HF stag e, indicating additional compensatory control at the translational or post-translational levels in the hypertrophied but non-failing ventric le. 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 progr am that is involved in the alterations in myocardial energy substrate utilization in the failing heart. The temporal correlation of diminish ed enzyme expression with onset of heart failure suggests that this al teration in lipid metabolism may play a role in the pathogenesis of pr essure-overload induced heart failure. This gene regulatory pathway sh ould be a useful target for experimental studies aimed at the molecula r pathogenesis of the transition from stable cardiac hypertrophy to ov ert heart failure.