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

He,Zhiqiang; Du,Xinyue; Wu,Yifan; Hua,Lingyue; Wan,Linxi; Yan,Nianlong

doi:10.3892/ijmm.2019.4310

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

Authors:
- Zhiqiang He
- Xinyue Du
- Yifan Wu
- Lingyue Hua
- Linxi Wan
- Nianlong Yan
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Affiliations: Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: August 9, 2019 https://doi.org/10.3892/ijmm.2019.4310
Pages: 1289-1298
Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Atherosclerosis is a major pathogenic factor in patients with cardiovascular diseases, and endothelial dysfunction (ED) plays a primary role in its occurrence and development. Simvastatin is a lipid‑lowering drug, which is commonly used to prevent or treat risk factors of cardiovascular diseases with a significant anti‑atherogenic effect. However, its impact on endothelial cells under conditions of oxidative stress and broader mechanisms of action remain unclear. The present study evaluated the effect of simvastatin on human umbilical vein endothelial cells (HUVECs) under oxidative stress with H2O2, and the associated mechanisms. At a high dose (1 µM), simvastatin exacerbated H2O2‑induced endothelial cell dysfunction. Moreover, inhibition of the Wnt/β‑catenin pathway by salinomycin significantly suppressed the simvastatin‑associated HUVEC dysfunction. Western blot analysis further demonstrated that simvastatin promoted the phosphorylation of low‑density lipoprotein receptor‑related protein 6 (LRP6) and activated the Wnt/β‑catenin pathway. Simvastatin also activated endoplasmic reticulum (ER) stress, which was reversed by salinomycin treatment. Based on these results, it was hypothesized that simvastatin may promote ER stress by facilitating LRP6 phosphorylation and the subsequent activation of the Wnt/β‑catenin pathway, thereby enhancing H2O2‑induced ED. Therefore, high‑dose simvastatin treatment could have potential toxic side effects, indicating the need for close clinical management, monitoring and patient selection.

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