Pm. Barger et Dp. Kelly, Fatty acid utilization in the hypertrophied and failing heart: Molecular regulatory mechanisms, AM J MED SC, 318(1), 1999, pp. 36-42
Citations number
30
Categorie Soggetti
General & Internal Medicine","Medical Research General Topics
During the development of cardiac hypertrophy and in the failing heart, the
chief myocardial energy source switches from Fatty acid P-oxidation to gly
colysis: a reversion to the fetal energy substrate preference pattern. This
review describes recent molecular studies aimed at delineating the gene re
gulatory pathway involved in the energy metabolic switch in the hypertrophi
ed heart and the potential role of the attendant metabolic consequences in
the pathogenesis of heart failure. Studies have been performed with the 'sp
ontaneous hypertensive and heart failure' rat strain and with human cardiom
yopathic tissue. These studies have demonstrated that expression of the gen
e that encodes medium-chain acyl-coenzyme A dehydrogenase (MCAD), a key fat
ty acid P-oxidation enzyme, is downregulated during the progression from ca
rdiac hypertrophy to ventricular dysfunction. A series of studies performed
in mice transgenic for the human MCAD gene promoter have identified a tran
scriptional regulatory pathway involved in the repression of MCAD gene expr
ession in the hypertrophied mouse heart. Two categories of transcription fa
ctors, nuclear hormone receptors and Sp factors, bind MCAD gene promoter re
gulatory elements in response to pressure overload to reactivate a fetal me
tabolic gene program. Studies are under way to manipulate this transcriptio
nal regulatory pathway in mice using genetic engineering strategies to dete
rmine whether this energy metabolic derangement plays a primary role in the
development of cardiac hypertrophy and heart failure.