Hu Dandan, Wang Litian, Qi Lin, Yang Xiangxuan, Jin Yamin, Yin Huailiu, Huang Yewei, Sheng Jun, Wang Xuanjun
Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, 650201, China.
College of Science, Yunnan Agricultural University, Kunming, 650201, China.
Lipids Health Dis. 2025 May 8;24(1):167. doi: 10.1186/s12944-025-02585-8.
Atherosclerosis (AS) is a complex and chronic vascular disease and elevated low-density lipoprotein cholesterol (LDL-C) level is one of its primary causative factors. As a key surface receptor, low-density lipoprotein receptor (LDLR) plays an essential role in LDL-C clearance. Resveratrol (RSV) has emerged as a promising compound for investigating potential therapeutic targets for AS due to its ability to lower cholesterol, reduce endothelial anti-inflammatory and suppress vascular smooth muscle cell proliferation. This study explored the effects of RSV on AS through upregulating LDLR and analyzed the mechanism through a combination of in vivo and vitro experiments.
HepG2 cells were exposed to varying concentrations of RSV. The effects of RSV on LDLR expression and cholesterol uptake were analyzed by western blot, RT-qPCR and DiI-LDL uptake assay. In vivo, C57BL/6J ApoE mice were used and the experimental groups were treated with RSV, Lovastatin and Gefitinib. Plaque formation in the arteries and aortic roots was assessed by Oil Red O staining and plaque stability was evaluated using Hematoxylin-Eosin (H&E) and Elastic Van Gieson (EVG) staining. Western blot, RT-qPCR and immunohistochemical staining were employed to analyze the expression of LDLR in the livers of mice.
RSV significantly enhanced the stability of LDLR mRNA and promoted LDLR protein expression. The inhibition experiments of EGFR signaling pathway (Cetuximab and Gefitinib) demonstrated that the efficacy of RSV was markedly weakened when this signaling pathway was inhibited. It indicated that RSV modulated LDLR gene expression by activating EGFR-ERK1/2 pathway. In ApoE mice, RSV notably reduced arterial plaque formation, improved plaque stability and increased hepatic LDLR expression.
This study elucidated the mechanism by which RSV upregulates LDLR gene expression through activating EGFR-ERK1/2 signaling pathway. In vivo experiments demonstrated its efficacy in reducing arterial plaque formation and stabilizing existing plaques. These results further indicated that RSV held potential therapeutic value for ameliorating atherosclerosis and cardiovascular diseases. Collectively, these findings provided novel theoretical support for RSV's potential role in cardiovascular therapy.
动脉粥样硬化（AS）是一种复杂的慢性血管疾病，低密度脂蛋白胆固醇（LDL-C）水平升高是其主要致病因素之一。作为关键的表面受体，低密度脂蛋白受体（LDLR）在LDL-C清除中起重要作用。白藜芦醇（RSV）因其降低胆固醇、减轻内皮抗炎和抑制血管平滑肌细胞增殖的能力，已成为研究AS潜在治疗靶点的有前景的化合物。本研究通过上调LDLR探讨RSV对AS的影响，并通过体内和体外实验相结合的方式分析其机制。
将HepG2细胞暴露于不同浓度的RSV中。通过蛋白质免疫印迹法、逆转录-定量聚合酶链反应（RT-qPCR）和DiI-LDL摄取试验分析RSV对LDLR表达和胆固醇摄取的影响。在体内，使用C57BL/6J ApoE小鼠，实验组分别用RSV、洛伐他汀和吉非替尼治疗。通过油红O染色评估动脉和主动脉根部的斑块形成，使用苏木精-伊红（H&E）和弹性范吉森（EVG）染色评估斑块稳定性。采用蛋白质免疫印迹法、RT-qPCR和免疫组织化学染色分析小鼠肝脏中LDLR的表达。
RSV显著增强LDLR mRNA的稳定性并促进LDLR蛋白表达。表皮生长因子受体（EGFR）信号通路抑制实验（西妥昔单抗和吉非替尼）表明，当该信号通路被抑制时，RSV的作用明显减弱。这表明RSV通过激活EGFR-ERK1/2通路调节LDLR基因表达。在ApoE小鼠中，RSV显著减少动脉斑块形成，改善斑块稳定性并增加肝脏LDLR表达。
本研究阐明了RSV通过激活EGFR-ERK1/2信号通路上调LDLR基因表达的机制。体内实验证明了其在减少动脉斑块形成和稳定现有斑块方面的疗效。这些结果进一步表明RSV在改善动脉粥样硬化和心血管疾病方面具有潜在的治疗价值。总的来说，这些发现为RSV在心血管治疗中的潜在作用提供了新的理论支持。
