Simvastatin Attenuates H2O2-Induced Endothelial Cell Dysfunction by Reducing Endoplasmic Reticulum Stress

Abstract

Atherosclerosis is the pathological basis of cardiovascular disease, whilst endothelial dysfunction (ED) plays a primary role in the occurrence and development of atherosclerosis. Simvastatin has been shown to possess significant anti-atherosclerosis activity. In this study, we evaluated the protective effect of simvastatin on endothelial cells under oxidative stress and elucidated its underlying mechanisms. Simvastatin was found to attenuate H2O2-induced human umbilical vein endothelial cells (HUVECs) dysfunction and inhibit the Wnt/β-catenin pathway; however, when this pathway was activated by lithium chloride, endothelial dysfunction was clearly enhanced. Further investigation revealed that simvastatin did not alter the expression or phosphorylation of LRP6, but reduced intracellular cholesterol deposition and inhibited endoplasmic reticulum (ER) stress. Inducing ER stress with tunicamycin activated the Wnt/β-catenin pathway, whereas reducing ER stress with 4-phenylbutyric acid inhibited it. We hypothesize that simvastatin does not affect transmembrane signal transduction in the Wnt/β-catenin pathway, but inhibits ER stress by reducing intracellular cholesterol accumulation, which blocks intracellular signal transduction in the Wnt/β-catenin pathway and ameliorates endothelial dysfunction.

Hydroxypropyl‑β‑cyclodextrin attenuates the epithelial‑to‑mesenchymal transition via endoplasmic reticulum stress in MDA‑MB‑231 breast cancer cells

“…In addition, other ER stress inducers, such as tunicamycin, can activate ER stress and then regulate the process of EMT; and inducing the ER stress can alter many other signaling pathways, including the AKT and MAPK signaling pathways (40) and the Wnt/β-catenin signaling pathway (41), therefore, further studies are required to compliment the present study. Although there are several studies that do not include a 4-PBA alone group (41–44), it would have been better if the present study had added a 4-PBA group to overcome the influence of 4-PBA on the experimental results. Collectively, the results of the present study suggested that HP-β-CD regulates the EMT through inhibition of the TGF-β/Smad signaling pathway, which then activates ER stress in MDA-MB-231 cells (Fig.…”

Endoplasmic Reticulum Stress Affects Cholesterol Homeostasis by Inhibiting LXRα Expression in Hepatocytes and Macrophages

“…For example, in vivo and in vitro studies demonstrate that saturated fatty acids promote ER stress [ 35 ]. Moreover, our previous results verified that cholesterol deposition could cause endothelial dysfunction by activating ER stress [ 36 , 37 ]. In this study, we proved that tunicamycin-induced ER stress elevated both the cholesterol and triglyceride content in Huh7 and THP-1 cells, and LXR-623 reversed these changes.…”

Simvastatin promotes endothelial dysfunction by activating the Wnt/β‑catenin pathway under oxidative stress

“…Conversely, cholesterol supplementation upregulates the expression of LRP6 and β-catenin (33). In fact, in our previous study, 0.2 µ M simvastatin had no effect on the expression or phosphorylation of LRP6, but reduced intracellular cholesterol deposition and inhibited ER stress (34). However, in the present study, 1 µ M simvastatin was used to inhibit cholesterol biosynthesis, increase LRP6 phosphorylation, and activate the Wnt/β-catenin pathway by decreasing β-catenin phosphorylation and degradation (Fig.…”

“…Therefore, further investigation of these pathways may provide a greater understanding of the results of the present study. Furthermore, animal experiments or clinical studies may contribute further knowledge in relation to the mechanism (34,40,41). Overall, the present results revealed a novel, alternative mechanism of action of simvastatin, demonstrating that it can promote LRP6 phosphorylation, thereby activating the Wnt/β-catenin pathway and promoting ER stress, ultimately enhancing H 2 O 2 -induced HUVEC dysfunction (Fig.…”