The Role of Thyroid Hormone Receptors in the Heart

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.