Thyroid hormone receptor α is a molecular switch of cardiac function between fetal and postnatal life

Abstract

Thyroid hormones are involved in the regulation of many physiological processes and regulate gene transcription by binding to their nuclear receptors TR␣ and TR␤. In the absence of triiodothyronine (T3), the unliganded receptors (aporeceptors) do bind DNA and repress the transcription of target genes. The role of thyroid hormone aporeceptors as repressors was observed in hypothyroid adult mice, but its physiological relevance in nonpathological hypothyroid conditions remained to be determined. Here we show that, in the normal mouse fetus, TR␣ aporeceptors repress heart rate as well as the expression of TR␤ and several genes encoding ion channels involved in cardiac contractile activity. Right after birth, when T3 concentration sharply increases, liganded TR␣ (holoreceptors) turn on the expression of some of these same genes concomitantly with heart rate increase. These data describe a physiological situation under which conversion of TR␣ from apo-receptors into holo-receptors, upon changes in T3 availability, plays a determinant role in a developmental process.

Triiodothyronine induces lipid oxidation and mitochondrial biogenesis in rat Harderian gland

“…It is well known that Thra and Thrb mRNAs are expressed in most rat tissues, although their relative abundance varies (Cheng et al 2010 for review). For example Thra1 is the major isoform expressed in the heart (Falcone et al 1992, Mai et al 2004, whereas Thrb1 predominates in the liver (Harvey & Williams 2002). In the brain, Thra1 is the major foetal isoform, but at birth, there is a marked increase in the expression of Thrb1, which is later maintained during adult life (Harvey & Williams 2002).…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…Development of the heart and transition of a fetal to adult cardiac gene expression program is to a large extent dependent on thyroid hormone (534). The heart remains a major target organ of thyroid hormone in adult life and cardiovascular effects are among the most pronounced clinical manifestations of hypothyroidism and thyrotoxicosis in man (535).…”

“…This specialized technique has been used in TR-mutant mice to study the effects of disruption of T 3 action on functional cardiac development in utero (534).…”

“…Certain aspects of fetal cardiac function can be assessed using color Doppler-guided spectral Doppler ultrasound (534). This specialized technique has been used in TR-mutant mice to study the effects of disruption of T 3 action on functional cardiac development in utero (534).…”

Benzofuran derivatives and the thyroid

“…13 The roles of TR α and TR β have been shown to be tissue-specific as well as functionally redundant. 16,17 For example, TR α mediates important T 3 actions during heart, bone and intestinal development and controls basal heart rate and thermoregulation in adults, 17,18 while TR β mediates T 3 action in liver 19 and is responsible for regulation of the HPT axis. 20 Detailed analysis of TR β indicates that TR β 1 is expressed in most tissues, whereas TR β 2 is restricted to the hypothalamus, pituitary, cochlea and retina.…”