Abstract
Over the past decade, endoplasmic reticulum (ER) stress has emerged as an important mechanism involved in the pathogenesis of cardiovascular diseases including heart failure. Cardiac therapy based on ER stress modulation is viewed as a promising avenue toward effective therapies for the diseased heart. Here, we tested whether sirtuin-1 (SIRT1), a NAD+-dependent deacetylase, participates in modulating ER stress response in the heart. Using cardiomyocytes and adult-inducible SIRT1 knockout mice, we demonstrate that SIRT1 inhibition or deficiency increases ER stress-induced cardiac injury, whereas activation of SIRT1 by the SIRT1-activating compound STAC-3 is protective. Analysis of the expression of markers of the three main branches of the unfolded protein response (i.e., PERK/eIF2α, ATF6 and IRE1) showed that SIRT1 protects cardiomyocytes from ER stress-induced apoptosis by attenuating PERK/eIF2α pathway activation. We also present evidence that SIRT1 physically interacts with and deacetylates eIF2α. Mass spectrometry analysis identified lysines K141 and K143 as the acetylation sites on eIF2α targeted by SIRT1. Furthermore, mutation of K143 to arginine to mimic eIF2α deacetylation confers protection against ER stress-induced apoptosis. Collectively, our findings indicate that eIF2α deacetylation on lysine K143 by SIRT1 is a novel regulatory mechanism for protecting cardiac cells from ER stress and suggest that activation of SIRT1 has potential as a therapeutic approach to protect the heart against ER stress-induced injury.
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Acknowledgements
We thank N Viet Hung for Mass Spectrometry analysis (SFR A Lwoff Platform). We also thank F Lefebvre for helpful technical assistance and Valérie Domergue-Dupont and the animal core facility of IPSIT for efficient handling and preparation of the animals. We gratefully acknowledge C Longin and S Chat for electron microscopy work (TEM platform of INRA). We thank Dr R Fischmeister for continuous support and careful reading of the manuscript. WT and mutant (S52A) eIF2α encoding plasmids were kindly provided by D Ron (University of Cambridge). This work was supported by grants from LabEx LERMIT, FRM (Fondation pour la Recherche Médicale) to A Garnier (#DPM20121125546) and Région Ile de France CODDIM to R Ventura-Clapier (#cod110153). A Prola received a fellowship from Groupe de Réflexion sur la Recherche Cardiovasculaire (GRRC). A Guilbert received a fellowship from Région Ile de France CORDDIM. D Sinclair is supported by the Glenn Foundation for Medical Research, a gift from the Schulak Family, the Juvenile Diabetes Foundation, and a MERIT award from the NIH/NIA.
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DAS consults for GlaxoSmithKline, Metrobiotech, Ovascience and BigDataBio. The remaining authors declare no conflict of interest.
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Prola, A., Pires Da Silva, J., Guilbert, A. et al. SIRT1 protects the heart from ER stress-induced cell death through eIF2α deacetylation. Cell Death Differ 24, 343–356 (2017). https://doi.org/10.1038/cdd.2016.138
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DOI: https://doi.org/10.1038/cdd.2016.138
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