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Effect of serum triiodothyronine on regulation of cardiac gene expression: role of histone acetylation

¹Department of Medicine and Institute for Medical Research, North Shore University Hospital, Manhasset; and ²Department of Cell Biology, New York University School of Medicine, New York, New York

Submitted 23 February 2005 ; accepted in final form 9 May 2005

Thyroid hormone regulates the transcription of several important cardiac genes. Although the thyroid gland produces predominantly thyroxine (T₄), it is triiodothyronine (T₃) that is transported across the sarcolemma and binds to nuclear thyroid hormone receptor proteins; yet various studies suggest that serum T₃ levels do not accurately reflect cellular T₃ action. To address this question, we studied the dose-response relationship of T₃ administered by constant infusion in hypothyroid animals with the simultaneous in vivo transcription rate of the cardiac-specific -myosin heavy chain (MHC) gene, measured by quantitating -MHC heteronuclear (hn)RNA content. Constant infusion of 4 µg T₃·kg body wt^–1·day^–1 for 3 days normalized serum T₃ and restored transcription to euthyroid levels; in contrast, daily injections of the same dose increased -MHC transcription by only 55% of that obtained by infusion. Although infusion of T₃ at 1.25 µg T₃·kg body wt^–1·day^–1 was not sufficient to restore serum T₃ to normal, it was capable of restoring transcription to normal at 3 days, but when administered for 12 days, transcription of -MHC was found to be 50% of euthyroid levels, demonstrating a decreased sensitivity to T₃ over time. Treatment with trichostatin A (TSA) to inhibit histone deacetylation increased levels of total nuclear acetylated histone H4 by almost 50% but was without effect on the real-time PCR measures of -MHC hnRNA. TSA administered together with T₃ (10 µg T₃/kg body wt) significantly increased transcription of -MHC after 30 h, thus demonstrating a potential role for histones as cofactors in the T₃ regulation of cardiac -MHC transcription.

heteronuclear RNA; thyroid hormone; transcription; trichostatin A