Abstract
Thyroid hormone (T3) is an important signaling molecule for cardiac function. Chronic exposure of the heart to either elevated levels of thyroid hormone (hyperthyroidism) or lower thyroid hormone levels (hypothyroidism) have profound effects on cardiac output. Hyperthyroidism increases the risk of cardiac failure dramatically, and hypothyroidism is associated with a diminished contractile performance of the heart, which is frequently compensated by cardiac hypertrophy. The molecular mechanisms that underlie these complex changes in cardiac performance, which are dependent on thyroid hormone are not yet fully understood. We and others have identified key target genes for thyroid hormone that are expressed in the heart and can account for some of the cardiac phenotypes observed in hyper- and hypothyroidism. Because there are reports that thyroid hormone may have so-called extranuclear effects, and there may also be the possibility of indirect effects of thyroid hormone on the heart, we set out to investigate the effects of a mutant thyroid hormone receptor β1 expressed in the heart. The mutated cDNA was originally cloned from a human patient by Usala et al. (1) and had been sequenced to reveal a 3 bp deletion at positions 1295-1297, which led to a deletion of a threonine at amino acid position 337. The mutated receptor was characterized to have a dominant negative effect when co-expressed with wild-type receptors, which could be explained by the inability of the mutated receptor to bind hormone, at the same time retaining the ability to bind to DNA.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Usala, S. J., Menke, J. B., Watson, T. L., et al. (1991) A homozygous deletion in the c-erbA b thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance: isolation and characterization of the mutant receptor. Mol. Endocrinol. 5, 327–335.
Robbins, J., Palermo, J., and Rindt, H. (1995) In vivo definition of a cardiac specific promoter and its potential utility in remodeling the heart. Ann. NYAcad. Sci. 752, 492–505.
Rindt, H., Subramaniam, A., and Robbins, J. (1995) An in vivo analysis of transcriptional elements in the mouse alpha-myosin heavy chain gene promoter. Transgenic Res. 4, 397–405.
Wickenden, A. D., Lee, P., Sah, R., Huang, Q., and Fishman, G. I., and Backx, P. H. (1999) Targeted expression of a dominant-negative K(v)4.2 K(+) channel subunit in the mouse heart. Circ. Res. 85, 1067–1076.
James, J., Zhang, Y., Osinska, H., et al. (2000) Transgenic modeling of a cardiac troponin I mutation linked to familial hypertrophic cardiomyopathy. Circ. Res. 87, 805–811.
Passman, R. S. and Fishman, G. I. (1994) Regulated expression of foreign genes in vivo after germline transfer. J. Clin. Invest. 94, 2421–2425.
Fishman, G. I. (1995) Conditional trangenics. Trends Cardiovasc. Med. 5, 211–217.
Yu, Z., Redfern, C. S., and Fishman, G. I. (1996) Conditional transgene expression in the heart. Circ. Res. 79, 691–697.
Redfern, C. H., Coward, P., Degtyarev, M. Y., et al. (1999) Conditional expression and signaling of a specifically designed Gi-coupled receptor in transgenic mice. Nat. Biotechnol. 17, 165–169.
Koya, D., Dennis, J. W., Warren, C. E., et al. (1999) Overexpression of core 2 N-acetylglycosaminyltransferase enhances cytokine actions and induces hypertrophic myocardium in transgenic mice. FASEB J. 13, 2329–2337.
Henderson, S. A., Spencer, M., Sen, A., Kumar, C., Siddiqui, M. A., and Chien, K. R. (1989) Structure, organization, and expression of the rat cardiac myosin light chain-2 gene. Identification of a 250-base pair fragment which confers cardiac-specific expression. J. Biol. Chem. 264, 18,142–18,148.
Hunter, J. J., Zhu, H., Lee, K. J., Kubalak, S., and Chien, K. R. (1993) Targeting gene expression to specific cardiovascular cell types in transgenic mice. Hyper-tension 22, 608–617.
Hunter, J. J., Tanaka, N., Rockman, H. A., Ross, J., Jr., and Chien, K. R. (1995) Ventricular expression of amLC-2v-ras fusion gene induces cardiac hypertrophy and selective diastolic dysfunction in transgenic mice. J. Biol. Chem. 270, 23,173–23,178.
Niwa, H., Yamamura, K., and Miyazaki, J. (1991) Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108, 193–199.
Gloss, B., Sayen, M. R., Trost, S. U., et al. (1999) Altered cardiac phenotype in transgenic mice carrying the delta337 threonine thyroid hormone receptor β mutant derived from the S family. Endocrinology 140, 897–902.
He, H., Giordano, F. J., Hilal-Dandan, R., et al. (1997) Overexpression of the rat sarcoplasmic reticulum Ca2+ATPase gene in the heart of transgenic mice accel-erates calcium transients and cardiac relaxation. J. Clin. Invest. 100, 380–389.
Weinberger, C., Thompson, C. C., Ong, E. S., Lebo, R., Gruol, D. J., and Evans, R. M. (1986) The c-erb-A gene encodes a thyroid hormone receptor. Nature 324, 641–646.
Murray, M. B., Zilz, N. D., McCreary, N. L., MacDonald, M. J., and Towle, H. C. (1988) Isolation and characterization of rat cDNA clones for two distinct thyroid hormone receptors. J. Biol. Chem. 263, 12,770–12,777.
Rohrer, D. K., Hartong, R., and Dillmann, W. H. (1991) Influence of thyroid hormone and retinoic acid on slow sarcoplasmic reticulum Ca2+ATPase and myosin heavy chain Α gene expression in cardiac myocytes. Delineation of cis-active DNA elements that confer responsiveness to thyroid hormone but not to retinoic acid. J. Biol. Chem. 266, 8638–8646.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2002 Humana Press Inc.
About this protocol
Cite this protocol
Dillmann, W.H., Gloss, B.R. (2002). The Role of Thyroid Hormone Receptors in the Heart. In: Baniahmad, A. (eds) Thyroid Hormone Receptors. Methods in Molecular Biology, vol 202. Humana Press. https://doi.org/10.1385/1-59259-174-4:55
Download citation
DOI: https://doi.org/10.1385/1-59259-174-4:55
Publisher Name: Humana Press
Print ISBN: 978-0-89603-995-7
Online ISBN: 978-1-59259-174-9
eBook Packages: Springer Protocols