Triiodothyronine Increases Brain Natriuretic Peptide (BNP) Gene Transcription and Amplifies Endothelin-dependent BNP Gene Transcription and Hypertrophy in Neonatal Rat Ventricular Myocytes

Abstract

Brain natriuretic peptide (BNP) gene expression is a well documented marker of hypertrophy in the cardiac myocyte. Triiodothyronine (T3), the bioactive form of thyroid hormone, triggers a unique form of hypertrophy in cardiac myocytes that accompanies the selective activation or suppression of specific gene targets. In this study, we show that the BNP gene is a target of T3 action. BNP secretion was increased 6-fold, BNP mRNA levels 3-fold, and BNP promoter activity 3–5-fold following T3 treatment. This was accompanied by an increase in myocyte size, sarcomeric organization, and protein synthesis. Of note, several of the responses to T3 synergized with those to the conventional hypertrophic agonist endothelin. The response to the liganded thyroid hormone receptor (TR) was mediated by an unusual thyroid hormone response element located between −1000 and −987 relative to the transcription start site. Both TR homodimers and TR·retinoid X receptor heterodimers associated with this element in an electrophoretic mobility shift assay. Protein fragments harboring the LXXLL motifs of the coactivators GRIP1 and SRC1 or TRAP220 interacted predominantly with the TR·retinoid X receptor heterodimeric pair in a ligand-dependent fashion. Both TR homodimers and heterodimers in the unliganded state selectively associated with glutathione S-transferase-nuclear receptor corepressor fragments harboring one of three receptor interaction domains containing the sequence (I/L)XX(I/V)I. These interactions were dissociated following the addition of T3. Collectively, these findings identify the BNP gene as a potential model for the investigation of TR-dependent gene regulation in the heart. Brain natriuretic peptide (BNP) gene expression is a well documented marker of hypertrophy in the cardiac myocyte. Triiodothyronine (T3), the bioactive form of thyroid hormone, triggers a unique form of hypertrophy in cardiac myocytes that accompanies the selective activation or suppression of specific gene targets. In this study, we show that the BNP gene is a target of T3 action. BNP secretion was increased 6-fold, BNP mRNA levels 3-fold, and BNP promoter activity 3–5-fold following T3 treatment. This was accompanied by an increase in myocyte size, sarcomeric organization, and protein synthesis. Of note, several of the responses to T3 synergized with those to the conventional hypertrophic agonist endothelin. The response to the liganded thyroid hormone receptor (TR) was mediated by an unusual thyroid hormone response element located between −1000 and −987 relative to the transcription start site. Both TR homodimers and TR·retinoid X receptor heterodimers associated with this element in an electrophoretic mobility shift assay. Protein fragments harboring the LXXLL motifs of the coactivators GRIP1 and SRC1 or TRAP220 interacted predominantly with the TR·retinoid X receptor heterodimeric pair in a ligand-dependent fashion. Both TR homodimers and heterodimers in the unliganded state selectively associated with glutathione S-transferase-nuclear receptor corepressor fragments harboring one of three receptor interaction domains containing the sequence (I/L)XX(I/V)I. These interactions were dissociated following the addition of T3. Collectively, these findings identify the BNP gene as a potential model for the investigation of TR-dependent gene regulation in the heart. triiodothyronine sarcoplasmic endoplasmic reticulum Ca2+-ATPase myosin heavy chain thyroid hormone receptor brain natriuretic peptide thyroid hormone response element retinoid X receptor nuclear receptor corepressor human phosphate-buffered saline glutathione S-transferase receptor interaction domain electrophoretic mobility shift assay endothelin direct repeat The heart is highly sensitive to the effects of thyroid hormone. Triiodothyronine (T3),1 the most active form of thyroid hormone, increases heart rate, cardiac contractility (direct and indirect effects), and cardiac output. Pathological states associated with either hypo- or hyperthyroidism display abnormalities in cardiac function that frequently contribute to the morbidity and mortality associated with these disorders (1Klein I. Ojamaa K. N. Engl. J. 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These the model and that thyroid hormone of the associated with and T3 to activation of hypertrophic in these the of myocytes with these is and by the of the hypertrophy of the myocytes with a increase in the the to increase the and of the The combination of an increase in cell and a increase in sarcomeric relative to either is that these to the changes that hypertrophy in to the findings K. Yonekura K. Ribeiro R.C. Eto Y. Aoyagi T. Baxter J.D. Camacho S.A. Bristow M.R. Long C.S. Simpson P.C. Circ. Res. 2001; 89: 591-598Crossref PubMed Scopus (169) Google Scholar) an of T3 and the hypertrophic agonist in protein in cardiac myocyte that T3 and in in thyroid genes in these T3 increased and levels and increased and and The combination of T3 and to an was of hypertrophy in with the gene expression in the that of T3 in In this study, and T3 in to expression of the BNP gene and activation of the that thyroid hormone and receptors in in gene expression. The the between and T3 a of the activity the to of the transcription start the the the to to the the in that the a response to of the that through the The this is in TR to of to the or of the with the K. Yonekura K. Ribeiro R.C. Eto Y. Aoyagi T. Baxter J.D. Camacho S.A. Bristow M.R. Long C.S. Simpson P.C. Circ. Res. 2001; 89: 591-598Crossref PubMed Scopus (169) Google Scholar) also TR effects in study, with and to and as well as myocyte size, the of the findings in the BNP gene to in the the of this is to of TR and to for this The TR with direct of the sequence in a K. Full Text PDF PubMed Scopus Google Scholar), been in the J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The that we in the BNP gene promoter to this The the to for TR and for to the either or for and the to of been in R. A. S. S. Glass C.K. PubMed Scopus Google Scholar, Ikeda M. R.A. A. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar, M. M. Endocrinology. 1994; PubMed Scopus Google Scholar), is that between and one of the to the for to the BNP in the to a in activity the that is by this is as a direct repeat with the with a The TR to this the that nuclear receptors this element to activate or BNP gene In that also with this element of this with regulation of the BNP promoter that the the is as as that for the the unusual of the BNP unliganded to BNP promoter the of suppression of promoter activity to the of the TR J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). unusual and heterodimeric to the in the unliganded the addition of the the as for M. J. Biol. Chem. Full Text PDF PubMed Google Scholar). 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Endocrinol. 2000; PubMed Scopus Google Scholar). these interactions to sequence in the in and in the in as well as the of a domain in this in that is in S. B. M. Mol. Endocrinol. 2001; PubMed Scopus Google Scholar). I. A. Glass C.K. Lazar Mol. Biol. 1996; PubMed Scopus Google Scholar) shown that the nuclear receptor with also for the motifs in these corepressor Collectively, these the that for interactions the of the of target genes and the regulation of a of in the that that selectively target specific In the BNP gene has been as a target for the liganded TR in the cardiac myocyte. The for this activity in the BNP promoter is the transcription start and the to with the TR and to and corepressor in This to an model for investigation of thyroid gene expression in the heart. to Wang for with a number of the