Transcriptional downregulation of a mitochondria!. fatty acid oxidation enzyme gene in response to ventricular pressure overload
Mitochondria! fatty acid oxidation (FAO) is the major source of energy in the adult mammalian heart. Previous studies have shown that energy production via the FAO pathway is reduced and glucose oxidation increased in the hypertrophiée) and failing heart. To explore this energy metabolic regulatory switch at the level of gene expression, we performed pulmonary artery banding (PAB) studies in mice transgenic for the promoter region of the gene encoding human medium-chain acyl-CoA dehydrogenase (MCAD), a rate-limiting enzyme in the FAO cycle, fused to a CAT reporter (MCADCAT.371). MCADCAT.371 contains a 560 bp human MCAD promoter fragment shown previously to be expressed abundantly in heart. PAB for 7 days resulted in marked right ventricular hypertrophy In all animals (n=16) [RV to body weight ratio t 90±10% compared to shamoperated transgenic controls (n=10)]. Endogenous mouse heart MCAD mRNA levels decreased by a mean of 87±6%*, CAT mRNA decreased by 80±14%*, and GAT enzymatic activity decreased by 78±21%* in the PAB group compared to controls (*p<0.05). MCAD and CAT mRNA levels were unchanged in the left ventricle. Expression of atrial natriuretic factor mRNA (a marker of ventricular hypertrophy) was markedly induced in RV of the PAB mice. In contrast, levels of mRNA encoding the glycolytic enzyme, glyceraldehyde phosphate dehydrogenase, were not significantly different in the RV groups. These data demonstrate that expression of a pivotal FAO enzyme gene is downregulated in the pressure-overloaded ventricle. Further elucidation of this gene regulatory pathway should identify the transcription factors and upstream signals involved in the control of energy production in the normal and failing heart.
Sack, MN; Disch, DL; Rader, TA; Rockman, HA; Kelly, DP
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