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*LIOTHYRONINE
Endocrinology Vol. 140, No. 2 897-902
Copyright © 1999 by The Endocrine Society

ARTICLES

Altered Cardiac Phenotype in Transgenic Mice Carrying the {Delta}337 Threonine Thyroid Hormone Receptor ß Mutant Derived from the S Family1

Bernd Gloss, M. Richard Sayen, Susanne U. Trost, Wolfgang F. Bluhm, Markus Meyer, Eric A. Swanson, Stephen J. Usala2 and Wolfgang H. Dillmann

Department of Medicine, Division of Endocrinology and Metabolism, University of California-San Diego, La Jolla, California 92093-0618

Address all correspondence and requests for reprints to: Wolfgang H. Dillmann, M.D., Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, California 92093-0618. E-mail: wdillman{at}ucsd.edu

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 ß1 (T3Rß1-{Delta}337T) 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 (MHC{alpha} and MHCß) 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 MHC{alpha} and SERCA2 were markedly down-regulated, MHCß 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 T3Rß mutant.




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