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Contribution of beta-arrestin signaling mediated by angiotensin II receptor type 1 in cardiomyocyte hypertrophy induced by T3.

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Author(s):
Caroline Antunes Lino
Total Authors: 1
Document type: Doctoral Thesis
Press: São Paulo.
Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
Defense date:
Examining board members:
Maria Luiza Morais Barreto de Chaves; Eliana Hiromi Akamine; Claudio Miguel da Costa Neto; Claudimara Ferini Pacicco Lotfi; Francisco de Assis Rocha Neves
Advisor: Maria Luiza Morais Barreto de Chaves
Abstract

Elevated levels of thyroid hormones (THs) are commonly associated with activation of the local renin angiotensin system and the development of cardiac hypertrophy. The involvement of the angiotensin II receptor type 1 (AT1R) in the hypertrophic effects of the THs was previously described. However, the mechanisms underlying this interaction are still unknown. AT1R belongs to the G-protein coupled receptor family and promotes its signal transduction by G-protein dependent and independent mechanisms. Recently, beta-arrestin signaling (G-protein independent) has been described as contributing to the hypertrophic response in different experimental models. Thus, the present study investigated the involvement of beta-arrestin signaling in the hypertrophic effects of THs mediated by AT1R, as well as the participation of ERK½ in this process. Primary cardiomyocytes cultures were stimulated with T3 (triiodothyronine; 15nM) for the induction of hypertrophy. Cardiomyocytes acutely treated with T3 (5-30 min) resulted in transient activation of ERK½, which was partially attenuated upon Losartan (1µM) administration, an AT1R antagonist. The contribution of ERK½ to cardiomyocyte hypertrophy was verified by using PD98059 (20µM), a MEK½ inhibitor, which prevented the transcription of hypertrophic markers. Immunoprecipitation assays revealed increased interaction between AT1R and beta-arrestin 2 under T3 stimulation, suggesting the recruitment of beta-arrestin 2 and, possibly, the internalization of AT1R. Through immunofluorescence and subcellular fractionation assays, T3 has been shown to stimulate AT1R translocation, enhancing its expression in the cardiomyocyte nucleus. In addition, both ERK½ activation and cardiomyocyte hypertrophy were sensitive to the inhibition of endocytosis, which was assessed by Concanavalin A (0.5µg/ml). Interfering RNA assays were efficient in demonstrating the involvement of beta-arrestin 2 in ERK½ activation and in T3-induced cardiomyocyte hypertrophy. Therefore, the results evidenced the involvement of beta-arrestin-2-dependent signaling in the activation of ERK½, through the AT1R, which contributes to the cardiomyocyte hypertrophy promoted by T3. (AU)