Mn. Sack et Dp. Kelly, THE ENERGY SUBSTRATE SWITCH DURING DEVELOPMENT OF HEART-FAILURE - GENE REGULATORY MECHANISMS (REVIEW), INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 1(1), 1998, pp. 17-24
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.