Canonical and Noncanonical Contribution of Thyroid Hormone Receptor Isoforms Alpha and Beta to Cardiac Hypertrophy and Heart Rate in Male Mice.
Thyroid
; 34(6): 785-795, 2024 Jun.
Article
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| MEDLINE
| ID: mdl-38757582
ABSTRACT
Background:
Stimulation of ventricular hypertrophy and heart rate are two major cardiac effects of thyroid hormone (TH). The aim of this study was to determine in vivo which TH receptor (TR)-α or ß-and which mode of TR action-canonical gene expression or DNA-binding independent noncanonical action-mediate these effects.Methods:
We compared global TRα and TRß knockout mice (TRαKO; TRßKO) with wild-type (WT) mice to determine the TR isoform responsible for T3 effects. The relevance of TR DNA binding was studied in mice with a mutation in the DNA-binding domain that selectively abrogates DNA binding and canonical TR action (TRαGS; TRßGS). Hearts were studied with echocardiography at baseline and after 7 weeks of T3 treatment. Gene expression was measured with real-time polymerase chain reaction. Heart rate was recorded with radiotelemetry transmitters for 7 weeks in untreated, hypothyroid, and T3-treated mice.Results:
T3 induced ventricular hypertrophy in WT and TRßKO mice, but not in TRαKO mice. Hypertrophy was also induced in TRαGS mice. Thus, hypertrophy is mostly mediated by noncanonical TRα action. Similarly, repression of Mhy7 occurred in WT and TRαGS mice. Basal heart rate was largely dependent on canonical TRα action. But responsiveness to hypothyroidism and T3 treatment as well as expression of pacemaker gene Hcn2 were still preserved in TRαKO mice, demonstrating that TRß could compensate for absence of TRα.Conclusions:
T3-induced cardiac hypertrophy could be attributed to noncanonical TRα action, whereas heart rate regulation was mediated by canonical TRα action. TRß could substitute for canonical but not noncanonical TRα action.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Tri-Iodotironina
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Cardiomegalia
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Camundongos Knockout
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Receptores alfa dos Hormônios Tireóideos
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Receptores beta dos Hormônios Tireóideos
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Frequência Cardíaca
Limite:
Animals
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article