Faculté de Pharmacie, UMR-S 1180, INSERM, Université Paris-Saclay, 5 Rue J-B Clément, 92296 Châtenay-Malabry, France.
Inserm, UMR-S 1180, Université Versailles St-Quentin, Université Paris-Saclay, 92296 Châtenay-Malabry, France.
Int J Mol Sci. 2022 Jun 14;23(12):6628. doi: 10.3390/ijms23126628.
Disturbances in Endoplasmic Reticulum (ER) homeostasis induce ER stress, which has been involved in the development and progression of various heart diseases, including arrhythmias, cardiac hypertrophy, ischemic heart diseases, dilated cardiomyopathy, and heart failure. A mild-to-moderate ER stress is considered beneficial and adaptative for heart functioning by engaging the pro-survival unfolded protein response (UPR) to restore normal ER function. By contrast, a severe or prolonged ER stress is detrimental by promoting cardiomyocyte apoptosis through hyperactivation of the UPR pathways. Previously, we have demonstrated that the NAD-dependent deacetylase SIRT1 is cardioprotective in response to severe ER stress by regulating the PERK pathway of the UPR, suggesting that activation of SIRT1 could protect against ER-stress-induced cardiac damage. The purpose of this study was to identify natural molecules able to alleviate ER stress and inhibit cardiomyocyte cell death through SIRT1 activation. Several phenolic compounds, abundant in vegetables, fruits, cereals, wine, and tea, were reported to stimulate the deacetylase activity of SIRT1. Here, we evaluated the cardioprotective effect of ten of these phenolic compounds against severe ER stress using cardiomyoblast cells and mice. Among the molecules tested, we showed that ferulic acid, pterostilbene, and tyrosol significantly protect cardiomyocytes and mice heart from cardiac alterations induced by severe ER stress. By studying the mechanisms involved, we showed that the activation of the PERK/eIF2α/ATF4/CHOP pathway of the UPR was reduced by ferulic acid, pterostilbene, and tyrosol under ER stress conditions, leading to a reduction in cardiomyocyte apoptosis. The protection afforded by these phenolic compounds was not directly related to their antioxidant activity but rather to their ability to increase SIRT1-mediated deacetylation of eIF2α. Taken together, our results suggest that ferulic acid, pterostilbene, and tyrosol are promising molecules to activate SIRT1 to protect the heart from the adverse effects of ER stress.
内质网（ER）稳态紊乱会诱导内质网应激，内质网应激与各种心脏病的发生和发展有关，包括心律失常、心肌肥厚、缺血性心脏病、扩张型心肌病和心力衰竭。轻度至中度内质网应激被认为对心脏功能有益和适应性，通过激活未折叠蛋白反应（UPR）的生存促进途径来恢复正常的 ER 功能。相比之下，严重或长期的内质网应激通过过度激活 UPR 途径促进心肌细胞凋亡，对心脏有害。以前，我们已经证明 NAD 依赖性去乙酰化酶 SIRT1 通过调节 UPR 的 PERK 途径对严重的内质网应激具有心脏保护作用，这表明激活 SIRT1 可以防止内质网应激引起的心脏损伤。本研究的目的是鉴定能够通过激活 SIRT1 减轻内质网应激和抑制心肌细胞死亡的天然分子。大量存在于蔬菜、水果、谷物、葡萄酒和茶中的几种酚类化合物被报道能刺激 SIRT1 的去乙酰化酶活性。在这里，我们使用心肌细胞和小鼠评估了这 10 种酚类化合物对严重内质网应激的心脏保护作用。在测试的分子中，我们表明阿魏酸、白藜芦醇和酪醇显著保护心肌细胞和小鼠心脏免受严重内质网应激引起的心脏改变。通过研究所涉及的机制，我们表明，在 ER 应激条件下，阿魏酸、白藜芦醇和酪醇可减少 UPR 的 PERK/eIF2α/ATF4/CHOP 途径的激活，从而减少心肌细胞凋亡。这些酚类化合物提供的保护与它们的抗氧化活性无关，而是与它们增加 SIRT1 介导的 eIF2α 去乙酰化的能力有关。总之，我们的研究结果表明，阿魏酸、白藜芦醇和酪醇是有前途的激活 SIRT1 以保护心脏免受内质网应激不利影响的分子。
