Gene Regulatory Mechanisms Governing Energy Metabolism during Cardiac Hypertrophic Growth

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Abstract
Studies in a variety of mammalian species, including humans, have demonstrated a reduction in fatty acid oxidation (FAO) and increased glucose utilization in pathologic cardiac hypertrophy, consistent with reinduction of the fetal energy metabolic program. This review describes results of recent molecular studies aimed at delineating the gene regulatory events which facilitate myocardial energy substrate switches during hypertrophic growth of the heart. Studies aimed at the characterization of transcriptional control mechanisms governing FAO enzyme gene expression in the cardiac myocyte have defined a central role for the fatty acid-activated nuclear receptor peroxisome proliferator-activated receptor α (PPARα). Cardiac FAO enzyme gene expression was shown to be coordinately downregulated in murine models of ventricular pressure overload, consistent with the energy substrate switch away from fatty acid utilization in the hypertrophied heart. Nuclear protein levels of PPARα decline in the ventricle in response to pressure overload, while several Sp and nuclear receptor transcription factors are induced to fetal levels, consistent with their binding to DNA as transcriptional repressors of rate-limiting FAO enzyme genes with hypertrophy. Knowledge of key components of this transcriptional regulatory pathway will allow for the development of genetic engineering strategies in mice that will modulate fatty acid oxidative flux and assist in defining whether energy metabolic derangements play a primary role in the development of pathologic cardiac hypertrophy and eventual progression to heart failure.