Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
Department of Pharmacy, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
Eur J Pharmacol. 2023 Oct 5;956:175938. doi: 10.1016/j.ejphar.2023.175938. Epub 2023 Aug 1.
Impaired endothelium-dependent vasodilation in atherosclerosis is a high-risk factor for myocardial infarction and ischemic stroke, and inflammation, necroptosis and apoptosis contribute to endothelial dysfunction in atherosclerosis. Although DL-3-n-butylphthalide (NBP) has been widely used in treating ischemic stroke, its effect on endothelium-dependent vasodilation remains unknown. This study aims to explore whether NBP is able to improve endothelium-dependent vasodilation in atherosclerosis and the underlying mechanisms. Male ApoE mice were fed with a high-fat diet (HFD) for 9-16 weeks to establish a model of atherosclerosis. NBP were given to the mice after eating HFD for 6 weeks and atorvastatin served as a positive control. The endothelium-dependent vasodilation, the blood flow velocity, the atherosclerotic lesion area, the serum levels of lipids, inflammatory cytokines and necroptosis-relevant proteins (RIPK1, RIPK3 and MLKL), and the endothelial necroptosis and apoptosis within the aorta were measured. Human umbilical vein endothelial cells (HUVECs) were incubated with oxidized low-density lipoprotein (ox-LDL) for 48 h to mimic endothelial injury in atherosclerosis, lactate dehydrogenase release, the ratio of necroptosis and apoptosis and the expression of necroptosis-relevant proteins were examined. Similar to atorvastatin, NBP improves endothelium-dependent vasodilation, decreases aortic flow velocity and reduces atherosclerotic lesion area in HFD-fed ApoE mice, concomitant with a reduction in serum lipids, inflammatory cytokines and necroptosis-relevant proteins, and endothelial necroptosis and apoptosis. Consistently, NBP inhibited necroptosis and apoptosis in ox-LDL-treated HUVECs. Based on these observations, we conclude that NBP exerts beneficial effects on improving the endothelium-dependent vasodilation in atherosclerosis via suppressing inflammation, endothelial necroptosis and apoptosis.
动脉粥样硬化中内皮依赖性血管舒张功能受损是心肌梗死和缺血性卒中的高危因素，炎症、坏死性凋亡和细胞凋亡导致动脉粥样硬化中的内皮功能障碍。虽然 DL-3-正丁基苯酞（NBP）已广泛用于治疗缺血性卒中，但它对内皮依赖性血管舒张的作用尚不清楚。本研究旨在探讨 NBP 是否能够改善动脉粥样硬化中的内皮依赖性血管舒张及其潜在机制。雄性 ApoE 小鼠用高脂肪饮食（HFD）喂养 9-16 周，建立动脉粥样硬化模型。在 HFD 喂养 6 周后给予小鼠 NBP，阿托伐他汀作为阳性对照。测量内皮依赖性血管舒张、血流速度、动脉粥样硬化病变面积、血脂水平、炎症细胞因子和坏死性凋亡相关蛋白（RIPK1、RIPK3 和 MLKL）以及主动脉内皮坏死性凋亡和凋亡。将人脐静脉内皮细胞（HUVEC）孵育 48 小时用氧化型低密度脂蛋白（ox-LDL）模拟动脉粥样硬化中的内皮损伤，检测乳酸脱氢酶释放、坏死性凋亡和凋亡的比例以及坏死性凋亡相关蛋白的表达。与阿托伐他汀相似，NBP 改善 HFD 喂养的 ApoE 小鼠的内皮依赖性血管舒张，降低主动脉血流速度，减少动脉粥样硬化病变面积，同时降低血清脂质、炎症细胞因子和坏死性凋亡相关蛋白，以及内皮坏死性凋亡和凋亡。一致地，NBP 抑制 ox-LDL 处理的 HUVEC 中的坏死性凋亡和凋亡。基于这些观察结果，我们得出结论，NBP 通过抑制炎症、内皮坏死性凋亡和凋亡对改善动脉粥样硬化中的内皮依赖性血管舒张具有有益作用。
