Abstract
Recent studies have evidenced the involvement of inflammation-related pathways to the development of cardiac hypertrophy and other consequences on the cardiovascular system, including the calcium-binding protein S100A8. However, this has never been investigated in the thyroid hormone (TH)-prompted cardiac hypertrophy. Thus, we aimed to test whether S100A8 and related signaling molecules, myeloid differentiation factor-88 (MyD88) and nuclear factor kappa B (NF-қB), could be associated with the cardiomyocyte hypertrophy induced by TH. Our results demonstrate that the S100A8/MyD88/NF-қB signaling pathway is activated in cardiomyocytes following TH stimulation. The knockdown of S100A8 and MyD88 indicates the contribution of those molecules to cardiomyocyte hypertrophy in response to TH, as evaluated by cell surface area, leucine incorporation assay, and gene expression. Furthermore, S100A8 and MyD88 are crucial mediators of NF-қB activation, which is also involved in the hypertrophic growth of TH-treated cardiomyocytes. Supporting the in vitro data, the contribution of NF-қB for TH-induced cardiac hypertrophy is confirmed in vivo, by using transgenic mice with cardiomyocyte-specific suppression of NF-қB. These data identify a novel pathway regulated by TH that mediates cardiomyocyte hypertrophy. However, the potential role of this new pathway in short and long-term cardiac effects of TH remains to be further investigated.
Key messages
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Inflammation-related signaling is activated by T3 in cardiomyocytes.
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S100A8 and MyD88 have a crucial role in cardiomyocyte hypertrophy by T3.
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S100A8 and MyD88 mediate NF-қB activation by T3.
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NF-қB contributes to T3-induced cardiac hypertrophy in vitro and in vivo
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Acknowledgements
The authors acknowledge that the 3M mice were generously provided by Dr. W. Keith Jones at Loyola University, Chicago. The authors also thank Marina R. Fevereiro for valuable technical assistance. This work was supported by Sao Paulo Research Foundation (FAPESP), grants #2011/23352-4, #2013/22480-4, and #2015/01166-5, and in part by the start-up funds from Texas A&M Health Science Center, College of Medicine and American Heart Association Grant-in-Aid (0835227 N) to S.G.
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The experiments were performed in accordance with NIH guidelines and were approved by the Biomedical Sciences Institute/USP Ethics Committee for Animal Research and the Institutional Animal Care and Use Committee at the Texas A&M Health Science Center and Scott & White Hospital.
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Takano, A.P.C., Munhoz, C.D., Moriscot, A.S. et al. S100A8/MYD88/NF-қB: a novel pathway involved in cardiomyocyte hypertrophy driven by thyroid hormone. J Mol Med 95, 671–682 (2017). https://doi.org/10.1007/s00109-017-1511-y
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DOI: https://doi.org/10.1007/s00109-017-1511-y