Department of Pathological Medicine Clinical Laboratory, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Second Road, 510080 Guangzhou, Guangdong Province, China.
Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Second Road, 510080 Guangzhou, Guangdong Province, China.
J Nutr Biochem. 2019 May;67:63-71. doi: 10.1016/j.jnutbio.2019.01.022. Epub 2019 Feb 10.
Endothelial dysfunction is an early and central feature of atherosclerosis. Dietary resveratrol (RSV), a class of flavonoid compounds, have been demonstrated to exert several beneficial effects on human body. In this study, we investigated the protective effects of RSV on high fat diet-induced endothelial dysfunction. Human aortic endothelial cells (HAECs) were treated with RSV to evaluate the gene expression of the endothelial nitric oxide synthase (eNOS). Apolipoprotein E (apoE) mice were fed a high-fat, high-cholesterol diet (HCD) or HCD supplemented with RSV for 8 weeks. Treatment of cultured HAECs with RSV dose-dependently upregulated the eNOS expression as assessed by quantitative RT-PCR and Western blot, respectively. In addition, RSV increased the promoter activity of the human eNOS gene, as determined by luciferase assays of the eNOS promoter gene. The cAMP-response element binding protein (CREB) was identified as the target transcription factor involved in the RSV mediated upregulation of eNOS expression. RSV increased phosphorylation of CREB through protein kinase A (PKA) activation, which induced a CREB-mediated upregulation of eNOS transcription. Consequently, RSV treatment significantly reversed the deleterious effects of oxidized LDL (oxLDL)-induced oxidative stress in HAECs. In vivo, treatment with RSV improves endothelial dysfunction and attenuates atherosclerotic plaque formation in apoE mice through PKA-CREB-dependent pathway. Our findings demonstrate that RSV has an effect of activating eNOS expression, contributing to the prevention of dyslipidemia-induced endothelial dysfunction and atherosclerosis.
内皮功能障碍是动脉粥样硬化的早期和核心特征。膳食白藜芦醇（RSV）是一类黄酮类化合物，已被证明对人体有多种有益作用。在这项研究中，我们研究了 RSV 对高脂饮食诱导的内皮功能障碍的保护作用。用 RSV 处理人主动脉内皮细胞（HAEC），以评估内皮型一氧化氮合酶（eNOS）的基因表达。用高脂肪、高胆固醇饮食（HCD）或 HCD 补充 RSV 喂养载脂蛋白 E（apoE）小鼠 8 周。用 RSV 处理培养的 HAEC 可分别通过定量 RT-PCR 和 Western blot 评估，剂量依赖性地上调 eNOS 表达。此外，RSV 通过 eNOS 启动子基因的荧光素酶测定，增加了人 eNOS 基因的启动子活性。cAMP 反应元件结合蛋白（CREB）被鉴定为 RSV 介导的 eNOS 表达上调所涉及的靶转录因子。RSV 通过蛋白激酶 A（PKA）激活增加 CREB 的磷酸化，从而诱导 CREB 介导的 eNOS 转录上调。因此，RSV 处理显著逆转了 oxLDL 诱导的氧化应激对 HAEC 的有害影响。在体内，通过 PKA-CREB 依赖性途径，RSV 治疗可改善 apoE 小鼠的内皮功能障碍，并减轻动脉粥样硬化斑块形成。我们的研究结果表明，RSV 具有激活 eNOS 表达的作用，有助于预防血脂异常诱导的内皮功能障碍和动脉粥样硬化。
