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Posttranscriptional regulation of myosin heavy chain expression in the heart by triiodothyronine

¹Division of Endocrinology and Department of Medicine, North Shore University Hospital/New York University School of Medicine and North Shore-LIJ Research Institute, Manhasset; and ²Department of Cell Biology, New York University School of Medicine, New York, New York

Submitted 30 August 2004 ; accepted in final form 13 October 2004

Triiodothyronine (T₃) regulates cardiac contractility in part by regulating the expression of several important cardiac myocyte genes. In the rat, the T₃-mediated induction of -myosin heavy chain (MHC) transcription in hypothyroid hearts is rapid, exhibiting zero-order kinetics, whereas the repression of -MHC in these same hearts is much slower. To elucidate the mechanism for T₃ transcriptional as well as posttranscriptional regulation of both MHC gene isoforms, we used an RT-PCR-based transcription assay and the RNA polymerase II inhibitor actinomycin D in an in vivo model to simultaneously measure specific - and -MHC heterogeneous nuclear RNA (hnRNA), mRNA kinetics, and MHC antisense RNA. In vivo actinomycin D treatment blocked -MHC transcription in euthyroid rats by >80% at 2 h and suggested a half-life of -MHC hnRNA of 1 h, whereas actinomycin D inhibited -MHC transcription in hypothyroid rats by >75% at 6 h, suggesting a significantly longer hnRNA half-life of 4 h. The effect of actinomycin D on -MHC transcription was independent of T₃. T₃ treatment in hypothyroid animals caused -MHC mRNA to decline more rapidly than -MHC hnRNA, demonstrating, for the first time, a posttranscriptional mechanism(s). The measured change in -MHC mRNA half-life indicates a T₃-mediated destabilization of -MHC mRNA. To understand the mechanism by which T₃ destabilizes -MHC mRNA, we measured -MHC antisense RNA. -MHC antisense RNA is present in euthyroid myocytes, but levels are not significant in hypothyroid myocytes. This differential expression may explain some of the effects of T₃ on MHC posttranscriptional regulation.

thyroid hormone; myocardium; gene transcription; actinomycin D; RNA stability; heterogeneous nuclear RNA

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