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

• Main Authors: Zhiqiang He, Xuanhong He, Menghan Liu, Lingyue Hua, Tian Wang, Qian Liu, Lai Chen, Nianlong Yan
• Format: Article
• Language: English
• Published: MDPI AG 2019-05-01
• Series: Molecules
• Subjects: endothelial cell dysfunction; endoplasmic reticulum stress; simvastatin; Wnt/β-catenin pathway
• Online Access: https://www.mdpi.com/1420-3049/24/9/1782

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.