Differential effect of Histone Deacetylase inhibition in neonatal and adult cardiocytes

Abstract

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate gene expression both by controlling the acetylation state of nucleosomal histones and by directly interacting with transcriptional factors. Deacetylation of nucleosomal histones by HDACs results in transcriptional repression. Class II HDACs have been shown to play a role in cardiac hypertrophy, but most of the work currently published on the molecular mechanisms of how specific HDACs mediate changes in cardiac growth and gene expression have been performed in neonatal cardiocytes. Our hypothesis is that HDACs have a very different effect on the regulation of gene expression and cardiac growth in neonatal cardiocytes than they do in the adult cardiocytes. In this report, we inhibited HDAC activity with trichostatin A (TSA) and examined the hypertrophic maker gene, artial natriuretic factor (ANF), expression and cell growth in both neonatal and adult cardiocytes. Our results showed that TSA inhibited the deacetylation of histone in both neonatal and adult cardiocytes. The expression of ANF was inhibited by TSA in neonatal cardiocytes. Surprisingly, ANF promoter activity is dramatically upregulated by TSA in adult cardiocytes. Treatment with TSA reduced S6 phosphorylation and decreased the level of protein synthesis in neonatal cardiocytes. TSA treatment acts synergistically with a-adrenergic stimulation in adult cardiocytes, resulting in an increasing of S6 phosphorylation and protein synthesis. We conclude that HDACs play a very different role in the regulation of gene expression and cardiac growth in neonatal versus adult cardiocytes.