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or ß1
Division of Endocrinology and Metabolism (B.G., S.U.T., W.F.B., E.A.S., W.H.D.), University of California, San Diego, La Jolla, California 92093; Departments of Physiology and Biophysics and Medicine (R.C., R.W., K.M.J., W.G.), University of Calgary, School of Medicine, Calgary, Alberta T2N 4N1, Canada; and Laboratoire de Biologie Moleculaire et Cellulaire (O.C., J.S.), Centre Nationale de la Recherche Scientifique, Ecole Normale Superieure de Lyon, 69364 Lyon, France
Address all correspondence and requests for reprints to: Wolfgang H. Dillmann, Division of Endocrinology and Metabolism, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0618. E-mail: wdillman{at}ucsd.edu
Cardiac myocytes express the two thyroid hormone receptors
(T3Rs), T3R
and T3Rß. However,
which isoform contributes to specific, T3-induced
alterations of cardiac function remains unclear. Here, we used
individual T3R isoform knockout (KO) mice to study the
effects of T3R and T3Rß in the heart. Our
findings indicate that potassium channel genes that code for
K+ channels involved in action potential repolarization,
like KV 4.2 and minK, are T3R targets. Both are markedly
regulated by thyroid status. The recently identified cyclic
nucleotide-gated channels, HCN2 and HCN4, are targets of
T3R and are unchanged in a euthyroid T3Rß
KO. However, these transcripts respond markedly to altered
T3 signaling concomitant with bradycardia in
T3R KO and hypothyroid animals, as well as tachycardia
in hyperthyroid T3Rß KO mice. SERCA2a and myosins are
T3 regulated and were also targets of T3R,
and the papillary muscles of KO animals showed a slowed rate of
force development. Because of the absence of significant cardiac
effects in euthyroid T3Rß KO mice, we determined
messenger RNA levels for both T3R and
T3Rß in the heart. We found that T3Rß is
present at a 1:3 ratio to T3R1. We conclude that
the cardiac phenotype regulated by T3 is predominantly
mediated by T3R and that the lack of T3R
cannot be compensated by T3Rß in the heart.
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H. C. van Beeren, W. M. C. Jong, E. Kaptein, T. J. Visser, O. Bakker, and W. M. Wiersinga Dronerarone Acts as a Selective Inhibitor of 3,5,3'-Triiodothyronine Binding to Thyroid Hormone Receptor-{alpha}1: In Vitro and in Vivo Evidence Endocrinology, February 1, 2003; 144(2): 552 - 558. [Abstract] [Full Text] [PDF]
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D. Forrest Editorial: Twists in the Tail--Change-of-Function Mutations in Thyroid Hormone Receptors Endocrinology, July 1, 2002; 143(7): 2466 - 2468. [Full Text] [PDF]
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B. Morte, J. Manzano, T. Scanlan, B. Vennstrom, and J. Bernal Deletion of the thyroid hormone receptor alpha 1 prevents the structural alterations of the cerebellum induced by hypothyroidism PNAS, March 19, 2002; 99(6): 3985 - 3989. [Abstract] [Full Text] [PDF]
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F. Flamant, A.-L. Poguet, M. Plateroti, O. Chassande, K. Gauthier, N. Streichenberger, A. Mansouri, and J. Samarut Congenital Hypothyroid Pax8-/- Mutant Mice Can Be Rescued by Inactivating the TR{alpha} Gene Mol. Endocrinol., January 1, 2002; 16(1): 24 - 32. [Abstract] [Full Text] [PDF]
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A. Mansen, F. Yu, D. Forrest, L. Larsson, and B. Vennstrom TRs Have Common and Isoform-Specific Functions in Regulation of the Cardiac Myosin Heavy Chain Genes Mol. Endocrinol., December 1, 2001; 15(12): 2106 - 2114. [Abstract] [Full Text] [PDF]
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C. Salto, J. M. Kindblom, C. Johansson, Z. Wang, H. Gullberg, K. Nordstrom, A. Mansen, C. Ohlsson, P. Thoren, D. Forrest, et al. Ablation of TR{alpha}2 and a Concomitant Overexpression of {alpha}1 Yields a Mixed Hypo- and Hyperthyroid Phenotype in Mice Mol. Endocrinol., December 1, 2001; 15(12): 2115 - 2128. [Abstract] [Full Text] [PDF]
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K. Kinugawa, K. Yonekura, R. C.J. Ribeiro, Y. Eto, T. Aoyagi, J. D. Baxter, S. A. Camacho, M. R. Bristow, C. S. Long, and P. C. Simpson Regulation of Thyroid Hormone Receptor Isoforms in Physiological and Pathological Cardiac Hypertrophy Circ. Res., September 28, 2001; 89(7): 591 - 598. [Abstract] [Full Text] [PDF]
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