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Angiotensin type 1 receptor mediates thyroid hormone-induced cardiomyocyte hypertrophy through the Akt/GSK-3β/mTOR signaling pathway

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Abstract

Several studies have implicated the renin angiotensin system in the cardiac hypertrophy induced by thyroid hormone. However, whether Angiotensin type 1 receptor (AT1R) is critically required to the development of T3-induced cardiomyocyte hypertrophy as well as whether the intracellular mechanisms that are triggered by AT1R are able to contribute to this hypertrophy model is unknown. To address these questions, we employed a selective small interfering RNA (siRNA, 50 nM) or an AT1R blocker (Losartan, 1 μM) to evaluate the specific role of this receptor in primary cultures of neonatal cardiomyocytes submitted to T3 (10 nM) treatment. The cardiomyocytes transfected with the AT1R siRNA presented reduced mRNA (90%, P < 0.001) and protein (70%, P < 0.001) expression of AT1R. The AT1R silencing and the AT1R blockade totally prevented the T3-induced cardiomyocyte hypertrophy, as evidenced by lower mRNA expression of atrial natriuretic factor (66%, P < 0.01) and skeletal α-actin (170%, P < 0.01) as well as by reduction in protein synthesis (85%, P < 0.001). The cardiomyocytes treated with T3 demonstrated a rapid activation of Akt/GSK-3β/mTOR signaling pathway, which was completely inhibited by the use of PI3K inhibitors (LY294002, 10 μM and Wortmannin, 200 nM). In addition, we demonstrated that the AT1R mediated the T3-induced activation of Akt/GSK-3β/mTOR signaling pathway, since the AT1R silencing and the AT1R blockade attenuated or totally prevented the activation of this signaling pathway. We also reported that local Angiotensin I/II (Ang I/II) levels (120%, P < 0.05) and the AT1R expression (180%, P < 0.05) were rapidly increased by T3 treatment. These data demonstrate for the first time that the AT1R is a critical mediator to the T3-induced cardiomyocyte hypertrophy as well as to the activation of Akt/GSK-3β/mTOR signaling pathway. These results represent a new insight into the mechanism of T3-induced cardiomyocyte hypertrophy, indicating that the Ang I/II-AT1R-Akt/GSK-3β/mTOR pathway corresponds to a potential mediator of the trophic effect exerted by T3 in cardiomyocytes.

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Acknowledgments

The authors would like to thank Natássia Vieira and Dr. Mayana Zatz, both from the Neuromuscular Disease Research Center of the Institute of Biosciences of the University of São Paulo, for their assistance in performing the flow cytometry. This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Foundation for the Support of Research in the State of São Paulo) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development).

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  1. Laboratory of Cellular Biology and Functional Anatomy, Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 2415, São Paulo, SP, 05508-900, Brazil

    Gabriela Placoná Diniz & Maria Luiza Morais Barreto-Chaves

  2. Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-900, Brazil

    Marcela Sorelli Carneiro-Ramos

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  1. Gabriela Placoná Diniz
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Diniz, G.P., Carneiro-Ramos, M.S. & Barreto-Chaves, M.L.M. Angiotensin type 1 receptor mediates thyroid hormone-induced cardiomyocyte hypertrophy through the Akt/GSK-3β/mTOR signaling pathway. Basic Res Cardiol 104, 653–667 (2009). https://doi.org/10.1007/s00395-009-0043-1

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