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Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?
Open AccessArticle

SIRT1 Protects the Heart from ER Stress-Induced Injury by Promoting eEF2K/eEF2-Dependent Autophagy

1
Université Paris-Saclay, Inserm, UMR-S 1180, 92296 Châtenay-Malabry, France
2
Institute of Experimental Endocrinology, Biomedical Centre SAS, 833 06 Bratislava, Slovakia
3
Université Versailles St-Quentin, Université Paris-Saclay, Inserm, UMR-S 1180, 92296 Châtenay-Malabry, France
*
Author to whom correspondence should be addressed.
Cells 2020, 9(2), 426; https://doi.org/10.3390/cells9020426
Received: 14 January 2020 / Revised: 6 February 2020 / Accepted: 7 February 2020 / Published: 12 February 2020
(This article belongs to the Special Issue The Role of Proteostasis Derailment in Cardiac Diseases)
Many recent studies have demonstrated the involvement of endoplasmic reticulum (ER) stress in the development of cardiac diseases and have suggested that modulation of ER stress response could be cardioprotective. Previously, we demonstrated that the deacetylase Sirtuin 1 (SIRT1) attenuates ER stress response and promotes cardiomyocyte survival. Here, we investigated whether and how autophagy plays a role in SIRT1-afforded cardioprotection against ER stress. The results revealed that protective autophagy was initiated before cell death in response to tunicamycin (TN)-induced ER stress in cardiac cells. SIRT1 inhibition decreased ER stress-induced autophagy, whereas its activation enhanced autophagy. In response to TN- or isoproterenol-induced ER stress, mice deficient for SIRT1 exhibited suppressed autophagy along with exacerbated cardiac dysfunction. At the molecular level, we found that in response to ER stress (i) the extinction of eEF2 or its kinase eEF2K not only reduced autophagy but further activated cell death, (ii) inhibition of SIRT1 inhibited the phosphorylation of eEF2, (iii) eIF2α co-immunoprecipitated with eEF2K, and (iv) knockdown of eIF2α reduced the phosphorylation of eEF2. Our results indicate that in response to ER stress, SIRT1 activation promotes cardiomyocyte survival by enhancing autophagy at least through activation of the eEF2K/eEF2 pathway.
Keywords: Sirtuin 1; endoplasmic reticulum stress; autophagy/mitophagy; cell death; cardioprotection Sirtuin 1; endoplasmic reticulum stress; autophagy/mitophagy; cell death; cardioprotection
MDPI and ACS Style

Pires Da Silva, J.; Monceaux, K.; Guilbert, A.; Gressette, M.; Piquereau, J.; Novotova, M.; Ventura-Clapier, R.; Garnier, A.; Lemaire, C. SIRT1 Protects the Heart from ER Stress-Induced Injury by Promoting eEF2K/eEF2-Dependent Autophagy. Cells 2020, 9, 426.

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