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Title: SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation.
Author: Palomer Tarridas, Francesc Xavier
Román-Azcona, M Silvia
Pizarro Delgado, Javier
Planavila Porta, Ana
Villarroya i Gombau, Francesc
Valenzuela Alcaraz, Brenda I.
Crispi Brillas, Fàtima
Sepúlveda Martínez, Álvaro
Miguel-Escalada, Irene
Ferrer, Jorge
Nistal, J Francisco
Garcia, Raquel
Davidson, Mercy M.
Barroso Fernández, Emma
Vázquez Carrera, Manuel
Keywords: Malalties cardiovasculars
Cardiovascular diseases
Issue Date: 7-Mar-2020
Publisher: Springer Nature
Abstract: Sirtuin 3 (SIRT3) is a deacetylase that modulates proteins that control metabolism and protects against oxidative stress. Modulation of SIRT3 activity has been proposed as a promising therapeutic target for ameliorating metabolic diseases and associated cardiac disturbances. In this study, we investigated the role of SIRT3 in inflammation and fibrosis in the heart using male mice with constitutive and systemic deletion of SIRT3 and human cardiac AC16 cells. SIRT3 knockout mice showed cardiac fibrosis and inflammation that was characterized by augmented transcriptional activity of AP-1. Consistent with this, SIRT3 overexpression in human and neonatal rat cardiomyocytes partially prevented the inflammatory and profibrotic response induced by TNF-alpha. Notably, these effects were associated with a decrease in the mRNA and protein levels of FOS and the DNA-binding activity of AP-1. Finally, we demonstrated that SIRT3 inhibits FOS transcription through specific histone H3 lysine K27 deacetylation at its promoter. These findings highlight an important function of SIRT3 in mediating the often intricate profibrotic and proinflammatory responses of cardiac cells through the modulation of the FOS/AP-1 pathway. Since fibrosis and inflammation are crucial in the progression of cardiac hypertrophy, heart failure, and diabetic cardiomyopathy, our results point to SIRT3 as a potential target for treating these diseases.
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It is part of: Signal Transduction and Targeted Therapy, 2020, vol. 5, p. 14
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ISSN: 2095-9907
Appears in Collections:Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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