Cardiac expression and function of thyroid hormone receptor beta and its PV mutant.

Thyroid hormone (T3) influences cardiac function, and mice with deletion of thyroid hormone receptor (TR)alpha have diminished cardiac function. TR alpha 1 represents 70% and TR beta 1 represents the remaining 30% of TR in ventricular myocytes, and its role in cardiac function is not well established. To determine the role of TR beta 1 in detail, we compared contractility in isolated perfused hearts from wild-type (WT) and TR beta knockout mice under normal and increased work load. TR beta knockout hearts showed contractile function similar to WT hearts at baseline and under conditions of enhanced demand. To gain insight into the role of TR beta, we used mice with a homozygous mutation in exon 10 of TR beta encoding the dominant negative PV mutant (TR beta PV) expressed from the endogenous TR beta promoter. TR beta PV 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 TR beta 1 in the pacemaker myocytes of the sinoatrial node was confirmed by quantitation of TR alpha 1 and TR beta 1 mRNA in sinoatrial node, which showed that TR beta 1 mRNA represents 27.5 +/- 1.6% of the ligand-binding isoforms of the TR. In summary, although TR beta is expressed at much lower levels in all regions of the heart than TR alpha 1, expression of the strong dominant negative TR beta PV mutant results in decreased contractile function and heart rate.