New insight into the mechanisms associated with the rapid effect of T₃ on AT1R expression.

Gabriela Placoná Diniz, Ana Paula Cremasco Takano, Erika Bruneto, Francemilson Goulart da Silva, Maria Tereza Nunes, Maria Luiza Morais Barreto-Chaves

Department of Anatomy and Department of Physiology, Institute of Biomedical Sciences, University of São Paulo, Avenida Prof. Lineu Prestes 2415, Cidade Universitária, São Paulo SP 05508-900, Brazil.

Journal of molecular endocrinology 2012 Aug

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The angiotensin II type 1 receptor (AT1R) is involved in the development of cardiac hypertrophy promoted by thyroid hormone. Recently, we demonstrated that triiodothyronine (T₃) rapidly increases AT1R mRNA and protein levels in cardiomyocyte cultures. However, the molecular mechanisms responsible for these rapid events are not yet known. In this study, we investigated the T₃ effect on AT1R mRNA polyadenylation in cultured cardiomyocytes as well as on the expression of microRNA-350 (miR-350), which targets AT1R mRNA. The transcriptional and translational actions mediated by T₃ on AT1R levels were also assessed. The total content of ubiquitinated proteins in cardiomyocytes treated with T₃ was investigated. Our data confirmed that T₃ rapidly raised AT1R mRNA and protein levels, as assessed by real-time PCR and western blotting respectively. The use of inhibitors of mRNA and protein synthesis prevented the rapid increase in AT1R protein levels mediated by T₃. In addition, T₃ rapidly increased the poly-A tail length of the AT1R mRNA, as determined by rapid amplification of cDNA ends poly-A test, and decreased the content of ubiquitinated proteins in cardiomyocytes. On the other hand, T₃ treatment increased miR-350 expression. In parallel with its transcriptional and translational effects on the AT1R, T₃ exerted a rapid posttranscriptional action on AT1R mRNA polyadenylation, which might be contributing to increase transcript stability, as well as on translational efficiency, resulting to the rapid increase in AT1R mRNA expression and protein levels. Finally, these results show, for the first time, that T₃ rapidly triggers distinct mechanisms, which might contribute to the regulation of AT1R levels in cardiomyocytes.

Citation

Gabriela Placoná Diniz, Ana Paula Cremasco Takano, Erika Bruneto, Francemilson Goulart da Silva, Maria Tereza Nunes, Maria Luiza Morais Barreto-Chaves. New insight into the mechanisms associated with the rapid effect of T₃ on AT1R expression. Journal of molecular endocrinology. 2012 Aug;49(1):11-20