Altered cardiac phenotype in transgenic mice carrying the Δ337 threonine thyroid hormone receptor β mutant derived from the S family

Bernd Gloss, M. Richard Sayen, Susanne U. Trost, Wolfgang F. Bluhm, Markus Meyer, Eric A. Swanson, Stephen J. Usala, Wolfgang H. Dillmann

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

The heart has been recognized as a major target of thyroid hormone action. Our study investigates both the regulation of cardiac-specific genes and contractile behavior of the heart in the presence of a mutant thyroid hormone receptor β1 (T3Rβ1-Δ337T) derived from the S kindred. The mutant receptor was originally identified in a patient with generalized resistance to thyroid hormone. Cardiac expression of the mutant receptor was achieved by a transgenic approach in mice. As the genes for myosin heavy chains (MHCα and MHCβ) and the cardiac sarcoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA2) are known to be regulated by T3, their cardiac expression was analyzed. The messenger RNA levels for MHCα and SERCA2 were markedly down-regulated, MHCβ messenger RNA was up-regulated. Although T3 levels were normal in these animals, this pattern of cardiac gene expression mimics a hypothyroid phenotype. Cardiac muscle contraction was significantly prolonged in papillary muscles from transgenic mice. The electrocardiogram of transgenic mice showed a substantial prolongation of the QRS interval. Changes in cardiac gene expression, cardiac muscle contractility, and electrocardiogram are compatible with a hypothyroid cardiac phenotype despite normal T3 levels, indicating a dominant negative effect of the T3Rβ mutant.

Original languageEnglish (US)
Pages (from-to)897-902
Number of pages6
JournalEndocrinology
Volume140
Issue number2
DOIs
StatePublished - 1999
Externally publishedYes

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