SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation

Signal Transduction and Targeted Therapy
Xavier PalomerManuel Vázquez-Carrera

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-α. 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 inflammatio...Continue Reading

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Citations

Jan 29, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Jie ChenJunwei Liu
Feb 20, 2021·The Korean Journal of Physiology & Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology·Jing ChengLi Liu
Sep 30, 2020·Journal of Cellular Physiology·Hui TaoXuan-Sheng Ding

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Methods Mentioned

BETA
nuclear translocation
biopsies
acetylation
immunoprecipitation
ChIP
coimmunoprecipitation
electrophoresis
PCR
AFM

Software Mentioned

GraphPad Prism
ImageJ

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