Triiodothyronine increases brain natriuretic peptide (BNP) gene transcription and amplifies endothelin-dependent BNP gene transcription and hypertrophy in neonatal rat ventricular myocytes

Faquan Liang, Paul Webb, Adhirai Marimuthu, Sumei Zhang, David G. Gardner

Research output: Contribution to journalArticle

64 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)15073-15083
Number of pages11
JournalJournal of Biological Chemistry
Volume278
Issue number17
DOIs
StatePublished - Apr 25 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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