Molecular characterization of myocardial fibrosis during hypothyroidism: Evidence for negative regulation of the pro-α1(I) collagen gene expression by thyroid hormone receptor

Wei Jan Chen, Ying-Shiung Lee, Kwang Huei Lin*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

64 Scopus citations

Abstract

The purpose of this study was to gain insights into the underlying mechanism of myocardial fibrosis during hypothyroidism. Treatment of cardiac fibroblasts with a medium lacking thyroid hormone led to a 47% increase in [3H]thymidine incorporation into the cell nuclei compared with that in untreated cells. Northern blot analysis of RNA from cardiac fibroblasts grown in a thyroid hormone depleted medium resulted in a 38% increase in the abundance of mRNA for pro-α1(I) collagen. At the protein level, the amount of type I collagen, as determined by immunoprecipitation, was increased either in the cell lysate (46%) of cardiac fibroblasts grown in a thyroid hormone depleted medium or in the medium (44%). The chimeric plasmid, ColCAT 3.6, contains the 5'-flanking region of the rat pro-αl(I) collagen gene (from bases -3520 to +115) fused to the chloramphenicol acetyltransferase (CAT) gene. The plasmid was cotransfected with thyroid hormone receptor (TR) expression plasmid into rat cardiac fibroblasts and COS-l cells (monkey mesangial cells). Cells transfected with the ColCAT plasmid in the presence of thyroid hormone (100 nM T3) had a significant decrease (39% in fibroblasts, P < 0.01; 52% in COS-1 cells, P < 0.001) in CAT activity when compared to cells not exposed to thyroid hormone. Transient co-transfection of TR with various pro-αl(I) collagen/CAT deletion constructs showed that T3-dependent repression was preserved with the deletion from 3520 bp of the flanking sequence to a 5' end point at position -224, indicating that a thyroid hormone-response element (TRE) was localized at the region -224 to +115. The TR-DNA binding assays demonstrated binding of the human TRβ1 to a fragment containing a proposed TRE located between position -35 and +115 in the 5'-flanking region of the rat pro-αl(I) collagen gene.

Original languageEnglish
Pages (from-to)45-55
Number of pages11
JournalMolecular and Cellular Endocrinology
Volume162
Issue number1-2
DOIs
StatePublished - 2000

Keywords

  • Hypothyroidism
  • Myocardial fibrosis
  • Pro-α1(I) collagen gene
  • Thyroid hormone
  • Thyroid hormone receptor
  • Thyroid hormone-response element

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