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  3. DL-3-n-butylphthalide improves the endothelium-dependent vasodilation in high-fat diet-fed ApoE-/- mice via suppressing inflammation, endothelial necroptosis and apoptosis

DL-3-n-butylphthalide improves the endothelium-dependent vasodilation in high-fat diet-fed ApoE-/- mice via suppressing inflammation, endothelial necroptosis and apoptosis

  • Eur J Pharmacol. 2023 Aug 1;956:175938. doi: 10.1016/j.ejphar.2023.175938.
Li-Qun Lu 1,  Nian-Sheng Li 1,  Ming-Rui Li 1,  Jiao-Yang Peng 1,  Li-Jing Tang 2,  Xiu-Ju Luo 3,  Jun Peng 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
  • 2 Department of Pharmacy, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
  • 3 Department of Laboratory Medicine, The Third Xiangya Hospital of Central South University, Changsha, 410013, China.
  • 4 Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China. Electronic address: junpeng@csu.edu.cn.
PMID: 37536623 DOI: 10.1016/j.ejphar.2023.175938
Abstract

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.

Keywords

Apoptosis; Atherosclerosis; DL-3-n-butylphthalide; Endothelium-dependent vasodilation; Inflammation; Necroptosis.

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