The Impact of a Non-Functional Thyroid Receptor Beta upon Triiodotironine-Induced Cardiac Hypertrophy in Mice
Cellular Physiology and Biochemistry
Background/Aims: Thyroid hormone (TH) signalling is critical for heart function. The heart expresses thyroid hormone receptors (THRs); THRα1 and THRβ1. We aimed to investigate the regulation mechanisms of the THRβ isoform, its association with gene expression changes and implications for cardiac function. Methods: The experiments were performed using adult male mice expressing TRβ Δ337T , which contains the Δ337T mutation of the human THRB gene and impairs ligand binding. Cardiac function and
... diac function and RNA expression were studied after hypoor hyperthyroidism inductions. T3-induced cardiac hypertrophy was not observed in TRβ Δ337T mice, showing the fundamental role of THRβ in cardiac hypertrophy. Results: We identified a group of independently regulated THRβ genes, which includes Adrb2, Myh7 and Hcn2 that were normally regulated by T3 in the TRβ Δ337T group. However, Adrb1, Myh6 and Atp2a2 were regulated via THRβ. The TRβ Δ337T mice exhibited a contractile deficit, decreased ejection fraction and stroke volume, as assessed by echocardiography. In our model, miR-208a and miR-199a may contribute to THRβ-mediated cardiac hypertrophy, as indicated by the absence of T3-regulated ventricular expression in TRβ Δ337T mice. Conclusion: THRβ has important role in the regulation of specific mRNA and miRNA in T3-induced cardiac hypertrophic growth and in the alteration of heart functions. Ethical Approval This study was approved by the ethics committee of the Health Sciences Centre, Federal University of Rio de Janeiro (#IBCCF1002). Animals Eight-to-twelve-week-old male mice were used. These mice were wild type (TRβ WT ) or homozygous (TRβ Δ337T ) for the Δ337T-Thrb mutation, and they were generated as previously described, based on a natural human mutation  . The genotyping of tail DNA was performed by a mismatched polymerase chain reaction (PCR) as described in our previous study  . Mice were maintained in plastic cages and on absorbent bedding under controlled temperature (24±1°C) and lighting (12 h light/dark cycle) conditions, with lights on at 07:00 h. Mice had free access to filtered water and standard chow (Bio-Tec, RJ, Brazil) during all experimental procedures, except during the induction of hypothyroidism, as described below. A total of 62 TRβ WT and 41 TRβ Δ337T mice were used in all experiments. Thirteen TRβ WT and 11 TRβ Δ337T mice were sacrificed by decapitation, and their sera and hearts were collected and stored at -70°C for baseline evaluation.