@article{10902/34034,
year = {2020},
url = {https://hdl.handle.net/10902/34034},
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-?. 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.},
organization = {ACKNOWLEDGEMENTS: This work was supported by funds from the Spanish Ministry of Economy and Competitiveness (SAF2015-64146-R and RTI2018-093999-B-100) and the “Fundació La Marató de TV3” to M.V.-C., and from the Instituto de Salud Carlos III (FIS PI15/01224) to J.F.N. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) and CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN) are initiatives of the Instituto de Salud Carlos III - Spanish Ministry of Economy and Competitiveness. The pcDNA4- myc-HisA-SIRT3 and pcDNA4-myc-HisA-H248Y-SIRT3 plasmids were a gift from Toren Finkel (Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA). We thank the University of Barcelona’s Language Advisory Service for their assistance.},
publisher = {Springer Nature},
publisher = {Signal Transduction and Targeted Therapy, 2020, 5, 14},
title = {SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation},
author = {Palomer, Xavier and Román-Azcona, Javier and Planavila, Ana and Villarroya, Francesc and Valenzuela-Alcaraz, Brenda and Crispi, Fátima and Sepúlveda-Martínez, Álvaro and Miguel-Escalada, Irene and Ferrer, Jorge and Nistal Herrera, Juan Francisco and García López, Raquel and Davidson, Mercy M. and Barroso, Emma and Vázquez-Carrera, Manuel},
}