Cardiac Thyroid Hormone Metabolism and Heart Failure

Abstract

The heart is a principal target of thyroid hormone, and a reduction of cardiac thyroid hormone signaling is thought to play a role in pathological ventricular remodeling and the development of heart failure. Studies in various rodent models of heart disease have identified increased activity of cardiac type III deiodinase as a possible cause of diminished levels and action of thyroid hormone. Recent data indicate novel mechanisms underlying the induction of this thyroid hormone-degrading enzyme in the heart as well as post-transcriptional regulation of its expression by microRNAs. In addition, the relevance of diminished thyroid hormone signaling for cardiac remodeling is suggested to include miRNA-mediated effects on pathological signaling pathways. These and other recent studies are reviewed and discussed in the context of other processes and factors that have been implicated in the reduction of cardiac thyroid hormone signaling in heart failure.

Keywords: Deiodinase; Heart failure; Thyroid hormone; Ventricular remodeling.

Fig. 1

Schematic summary of some of the processes and factors involved in the homeostasis and action of T3 in cardiomyocytes. Dashed lines indicate possible, but not yet confirmed interactions. The monocarboxylate transporters MCT8 and MCT10 mediate the uptake of both T4 and T3, and T4 may be converted to T3 by deiodinase type 2 (DIO2). The T3 receptor (TR) mediates transcriptional effects that include proteins involved in calcium homeostasis (SERCA2a, PLN) and contraction (MHCα, MHCβ) as well as miRNAs that may modulate other signal transduction routes. Cytosolic TR mediates a stimulatory effect of T3 on a signaling cascade involved in physiological hypertrophy (PI3K/p85, Akt, mTOR). Deiodinase type 3 (DIO3) inactivates T3. Expression of DIO3 from the genomic DLK1-DIO3 imprinted region is stimulated by proliferative signals and signaling cascades involved in pathological hypertrophy (sonic hedgehog [SHH], GLI; transforming growth factor β [TGFβ], SMAD; hypoxia-inducible fac­tor-1α [HIF1α] and MAPK). Expression of DIO3 is limited by miR-214 and possibly by miR-21 acting through GRHL. See text for details.