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47 REVERSING THE FETAL GENE PROGRAM IN THE SETTING OF PATHOLOGIC STIMULI IMPROVES CARDIOMYOCYTE FUNCTION.
  1. M. Y. Jeong1,
  2. W. S. Colucci2,
  3. C. S. Long1
  1. 1University of Colorado Health Sciences Center, Denver, CO
  2. 2Boston University Medical Center, Boston, MA.

Abstract

Background Previously we found that abrogating activator protein 1 (AP-1) in neonatal rat ventricular myocytes subjected to pathologic stimuli resulted in reversal of the pathologic/fetal gene profile while maintaining agonist-induced myocyte hypertrophy. We now extend these observations to the adult rat cardiomyocyte (ARVM) and further investigate if reversing the gene program toward a physiologic profile in a pathologic model results in improved myocyte function.

Methods and Results Hypertrophy was induced in cultured ARVMs using norepinephrine with propranolol pretreatment. Induction of the pathologic gene profile was observed, ie, expression of beta-myosin heavy chain (betaMHC), and atrial/brain natriuretic peptides (ANP/BNP) was increased, whereas expression for the alpha-myosin heavy chain (alphaMHC) and sarcoplasmic reticulum Ca2+-ATPase (SERCA) genes was repressed. As with the neonatal cardiomyocyte experiments, the role of AP-1 in the hypertrophic phenotype was evaluated with the use of an adenoviral construct expressing a dominant negative mutant of the c-Fos proto-oncogene (AdAFos). Although AdAFos infection did not change the myocyte growth response, it resulted in the reversal of the gene profile to alpha-adrenergic stimulation, ie, up-regulation of alphaMHC/SERCA and repression of betaMHC and ANP/BNP. Translation of both MHC and SERCA proteins corresponded with their gene expression. Further, ARVM infected with Ad-AFos showed improved myocyte shortening, a surrogate marker for contractile function.

Conclusion Abrogation of AP-1 transcription factor in the setting of alpha-adrenergic stimulation results in improved cardiomyocyte function.

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