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

Li-Qun Lu; Nian-Sheng Li; Ming-Rui Li; Jiao-Yang Peng; Li-Jing Tang; Xiu-Ju Luo; Jun Peng

doi:10.1016/j.ejphar.2023.175938

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 Oct 5:956:175938. doi: 10.1016/j.ejphar.2023.175938. Epub 2023 Aug 1.

Authors

Li-Qun Lu¹, Nian-Sheng Li¹, Ming-Rui Li¹, Jiao-Yang Peng¹, Li-Jing Tang², Xiu-Ju Luo³, Jun Peng⁴

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.

MeSH terms

Animals
Apolipoproteins E / genetics
Apoptosis
Atherosclerosis* / metabolism
Atorvastatin / pharmacology
Cytokines / metabolism
Diet, High-Fat / adverse effects
Endothelium / metabolism
Human Umbilical Vein Endothelial Cells
Humans
Inflammation / metabolism
Ischemic Stroke* / metabolism
Male
Mice
Mice, Knockout
Necroptosis
Vasodilation

Substances

3-n-butylphthalide
Atorvastatin
Cytokines
Apolipoproteins E