Article Text

  1. S. O. Weiss,
  2. C. C. Sucharov,
  3. C. S. Long;
  1. University of Colorado Health Sciences Center, Denver, CO


Background For prognostic purposes, cardiac hypertrophy has been classified as either physiologic/normal or pathologic/abnormal. Although gross inspection of the heart is identical in these two conditions, the gene program is not and serves as a marker of pathologic stress. Specifically, physiologic hypertrophy is characterized by an increase in adult-specific genes such as αMHC and SERCA, while pathologic growth is typified by induction of fetal genes like βMHC and repression of adult-specific genes. Although a wealth of data exists on specific transcription factors involved in this process, chromatin modification by the histone acetyltransferases (HATs) and histone deacetylases (HDACs) has only recently been shown to play a substantive role in regulating cardiomyocyte genes. Generally, HAT activity is associated with a more differentiated gene program and HDAC activity is associated with a less differentiated phenotype. Since the pathologic gene program could be viewed as less differentiated, we hypothesized that inhibiting HDACs might cause a re-differentiation to the adult phenotype in the context of pathologic hypertrophy.

Methods and Results Neonatal rat ventricular myocytes in cell culture were treated with increasing concentrations of trichostatin A (TSA, 0-50 nM) in the presence or absence of phenylepherine (PE, 10 μM), a pathologic hypertrophic agent, or thyroid hormone (T3, 100 nM), a physiologic agonist. Growth was measured by radiolabeled protein analysis and gene program evaluated by ribonuclease protection assay. As expected, PE induced fetal genes and myocyte growth but decreased adult-specific genes. Although co-treatment with TSA had no effect on the PE growth response, it blunted repression of both SERCA and αMHC. In contrast, TSA inhibited the T3 growth response but did not alter induction of the adult-specific genes by this agent.

Conclusions Chromatin modification plays a vital role in the regulation of cardiac growth and gene program. Interestingly, HDAC inhibition uncouples the growth response from gene expression in models of pathologic and physiologic hypertrophy. This differential regulation could be exploited in the future treatment of pathologic myocardial growth.

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