Natural activators of SIRT1 protect cardiac cells from severe ER stress

Abstract

Perturbations of endoplasmic reticulum (ER) functions result in the accumulation of misfolded proteins inside the ER lumen, a condition known as ER stress. As a compensatory pro-survival response, the unfolded protein response (UPR) is activated to restore normal ER function. However, in the case of severe or chronic ER stress, apoptosis is triggered to eliminate damaged cells. Recently, ER stress was implicated in the pathogenesis of various heart diseases including heart failure (HF). Previously, we have shown that SIRT1 is cardioprotective against severe ER stress by regulating the PERK pathway of the UPR, suggesting that activation of SIRT1 could be effective to limit cardiac ER stress. Different natural polyphenols have been shown to activate SIRT1 in a variety of models. In this study, we thus evaluated the protective effect of 11 polyphenols (butein, fisetin, catechin…) that have been reported to activate SIRT1, against severe ER stress-induced cardiac cell death. Tunicamycin (TN), an inhibitor of N-glycosylation of proteins, was used to induce a severe ER stress in H9c2 cardiomyoblasts and adult rat ventricle myocytes (ARVM). Cell death was determined by fluorescence microscopy and flow cytometry and ER stress was analysed by western blot. As expected, TN induced an increase of the ER stress markers GRP78, GRP94 and the pro-apoptotic transcription factor CHOP associated with cardiac cell death. Three of the tested polyphenols were shown to protect H9c2 cells and ARVM against cell death induced by TN. Protection was abrogated when SIRT1 was inhibited by EX527. In addition, the level of the pro-apoptotic factor CHOP was reduced with polyphenols. These results indicated that among the 11 polyphenols tested, 3 were able to protect cardiac cells from ER stress-induced cell death in a SIRT1-dependent manner. Activation of SIRT1 by selected polyphenols thus appears as a promising strategy to modulate ER stress and protect cardiac cells.