Triiodothyronine increases brain natriuretic peptide (BNP) gene transcription and amplifies endothelin-dependent BNP gene transcription and hypertrophy in neonatal rat ventricular myocytes.
Brain natriuretic peptide (BNP) gene expression is a well documented marker of hypertrophy in the cardiac myocyte. Triiodothyronine (T(3)), 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 T(3) action. BNP secretion was increased 6-fold, BNP mRNA levels 3-fold, and BNP promoter activity 3-5-fold following T(3) treatment. This was accompanied by an increase in myocyte size, sarcomeric organization, and protein synthesis. Of note, several of the responses to T(3) 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 T(3). Collectively, these findings identify the BNP gene as a potential model for the investigation of TR-dependent gene regulation in the heart.
Liang
Faquan
F
Diabetes Center/Metabolic Research Unit and the Department of Medicine, University of California, San Francisco, California 94143-0540, USA.
Webb
Paul
P
Marimuthu
Adhirai
A
Zhang
Sumei
S
Gardner
David G
DG
D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000139:chemically induced*; D004357:Drug Synergism; D016232:Endothelins / Q000494:pharmacology*; D006352:Heart Ventricles / Q000166:cytology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014284:Triiodothyronine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D016232:Endothelins; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D020097:Natriuretic Peptide, Brain; C040407:3,3',5-triiodothyronamine