Fatty acid utilization in the hypertrophied and failing heart: molecular regulatory mechanisms.
During the development of cardiac hypertrophy and in the failing heart, the chief myocardial energy source switches from fatty acid beta-oxidation to glycolysis: a reversion to the fetal energy substrate preference pattern. This review describes recent molecular studies aimed at delineating the gene regulatory pathway involved in the energy metabolic switch in the hypertrophied heart and the potential role of the attendant metabolic consequences in the pathogenesis of heart failure. Studies have been performed with the 'spontaneous hypertensive and heart failure' rat strain and with human cardiomyopathic tissue. These studies have demonstrated that expression of the gene that encodes medium-chain acyl-coenzyme A dehydrogenase (MCAD), a key fatty acid beta-oxidation enzyme, is down-regulated during the progression from cardiac hypertrophy to ventricular dysfunction. A series of studies performed in mice transgenic for the human MCAD gene promoter have identified a transcriptional regulatory pathway involved in the repression of MCAD gene expression in the hypertrophied mouse heart. Two categories of transcription factors, nuclear hormone receptors and Sp factors, bind MCAD gene promoter regulatory elements in response to pressure overload to reactivate a fetal metabolic gene program. Studies are under way to manipulate this transcriptional regulatory pathway in mice using genetic engineering strategies to determine whether this energy metabolic derangement plays a primary role in the development of cardiac hypertrophy and heart failure.
Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
P M
PM
Barger
D P
DP
Kelly
D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D006019:Glycolysis; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans
D005227:Fatty Acids