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Division of Endocrinology and Metabolism (E.A.S., B.G., D.D.B., W.H.D.), University of California San Diego, La Jolla, California 92093 and Laboratory of Molecular Biology (M.K., S.C.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
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.
Thyroid hormone (T3) influences cardiac function, and mice with deletion of thyroid hormone receptor (TR)
have diminished cardiac function. TR1 represents 70% and TRß1 represents the remaining 30% of TR in ventricular myocytes, and its role in cardiac function is not well established. To determine the role of TRß1 in detail, we compared contractility in isolated perfused hearts from wild-type (WT) and TRß knockout mice under normal and increased work load. TRß knockout hearts showed contractile function similar to WT hearts at baseline and under conditions of enhanced demand. To gain insight into the role of TRß, we used mice with a homozygous mutation in exon 10 of TRß encoding the dominant negative PV mutant (TRßPV) expressed from the endogenous TRß promoter. TRßPV mice treated with 6-propyl-2-thiouracil and supplemented with T3 to make them euthyroid have decreased contractility with negative and positive rates of relaxation and contraction as well as peak systolic pressure diminished by 35 ± 5, 34 ± 6, and 35 ± 6% in comparison with WT mice. Heart rate is diminished by 36 ± 7%, which is accompanied by decreased expression of the pacemaker-related gene hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4). The expression of TRß1 in the pacemaker myocytes of the sinoatrial node was confirmed by quantitation of TR1 and TRß1 mRNA in sinoatrial node, which showed that TRß1 mRNA represents 27.5 ± 1.6% of the ligand-binding isoforms of the TR. In summary, although TRß is expressed at much lower levels in all regions of the heart than TR1, expression of the strong dominant negative TRßPV mutant results in decreased contractile function and heart rate.
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