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

Abstract

Danzi, Sara, Peter Dubon, and Irwin Klein. Effect of serum triiodothyronine on regulation of cardiac gene expression: role of histone acetylation. Am J Physiol Heart Circ Physiol 289: H1506 -H1511, 2005. First published May 13, 2005; doi:10.1152/ajpheart.00182.2005.-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 T 3 levels do not accurately reflect cellular T 3 action. To address this question, we studied the dose-response relationship of T 3 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 g T 3 ⅐ kg body wt Ϫ1 ⅐ day Ϫ1 for 3 days normalized serum T 3 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 T 3 at 1.25 g T 3 ⅐ kg body wt Ϫ1 ⅐ day Ϫ1 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 T 3 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 T 3 (10 g T3/kg body wt) significantly increased transcription of ␣-MHC after 30 h, thus demonstrating a potential role for histones as cofactors in the T 3 regulation of cardiac ␣-MHC transcription. heteronuclear RNA; thyroid hormone; transcription; trichostatin A THYROID HORMONE EXERTS well-defined effects on the heart and the cardiovascular system (16). Triiodothyronine (T 3 ) has been shown to act on the cardiac myocyte via genomic (nuclear) and nongenomic pathways (11,16). The cellular genomic mechanisms of T 3 action on positively regulated myocyte genes [␣-myosin heavy chain (MHC) and sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA)2] have been well described (11,20). T 3 binds to nuclear thyroid hormone receptors (TRs), which in turn bind to thyroid hormone response elements in the promoter region of thyroid hormone-responsive genes. In the presence of T 3 , TRs activate transcription by recruiting coactivator complexes, and in the absence of T 3 , TRs repress transcription by recruiting corepressor complexes (29). Despite the fact that T 3 is the biologically active form of thyroid hormone, studies have shown that normalizing serum T 3 in hypothyroid animals by administration of thyroxine (T 4 ), T 3 , or a combination of T 4 and T 3 does not necessarily normalize T 3 content...

Protein Acetylation in the Cardiorenal Axis

“…57,58 Notably, TSA has been shown to not only increase expression of cardiac ␣-MyHC in hypothyroid rats, 59 but also to potentiate the ability of thyroid hormone to drive ␣-MyHC expression. 60 In addition, a role for the Egr1 transcription factor in HDACi-mediated induction of the ␣-MyHC gene has been reported. 59 The Krüppel-like factor (Klf)4 transcription factor appears to represent another cardiac protective gene that is derepressed by HDACis.…”

Factors controlling cardiac myosin-isoform shift during hypertrophy and heart failure

“…There is also evidence that the effect of TRs on MHC gene transcription is controlled by direct or indirect association of the receptor with HAT and HDACs. Danzi et al have shown that the TSA-mediated induction of αMHC expression occurs only in euthyroid, but not in hypothyroid animals, suggesting a role of thyroid-signaling in the induction of αMHC expression by TSA [132]. Based on studies with other T3-responsive genes, it has been proposed that class-I HDACs binds to a co-repressor complex which associates with the un-ligand-TR complex on the hormone responsive DNA binding site, leading to repression of gene transcription.…”

Cardiac myosin heavy chain gene regulation by thyroid hormone involves altered histone modifications

“…A potential role of histone acetylation was demonstrated in T 3 regulation of cardiac ␣-MHC gene expression in adult male rats (11). Treatment with trichostatin A (TSA), a histone deacetylase inhibitor, was not effective in altering cardiac MHC expression in the absence of T 3 .…”