When the Thyroid Speaks, the Heart Listens

Thyroid hormone (TH, triiodothyronine, T3) signaling is critical for proper heart development and function. Myocyte-specific genes regulated by TH comprise a “who’s who” list of proteins responsible for cardiomyocyte function: myosin heavy chain (MHC), sarcoplasmic reticulum calcium-activated ATPase (SERCA), phospholamban, α- and β-adrenergic receptors, adenyl cyclase, protein kinase C, and a variety of ion channels. With this list of players, it is not surprising that alterations in TH stimulation have significant consequences for cardiac function including heart rate, contractility, and mass. The multiple effects of TH upon function of the cardiovascular system were recently summarized in an excellent review.1 The importance of regulating TH stimulation during the process of normal cardiac development has been established, particularly with regard to postnatal changes. Maturation of the myocardium depends upon increasing TH signaling after birth, which induces growth and the transcriptional reprogramming that leads to the characteristic gene expression profile of the adult heart. More than a decade has passed since initial reports showed the gene expression profile of the fetal heart (where TH stimulation is relatively low) was recapitulated in the hypertrophic and/or failing myocardium. This seminal observation suggestive of dysfunctional TH signaling spawned numerous investigations to examine the potential benefit of manipulating TH signaling to mitigate heart failure.2 However, using TH in a therapeutic context to combat reactivation of fetal gene expression in the failing heart may be hampered by altered expression of the appropriate thyroid receptors (TRs) needed to transduce TH signals. Two TR isoforms, designated TRα1 and TRβ1, which can bind TH with similar affinity, are present within the heart. A third isoform, TRα2, is a splice variant of TRα1 that does not bind TH and can act as a dominant-negative protein for TR signaling. Significance of a fourth isoform, TRβ2, remains unresolved since low levels …