ligustilide and Atherosclerosis

Ligustilide (LIG) is a major active ingredient in traditional Chinese medicines that is also found in plant rhizomes such as carrot, coriander, and others, and it has been demonstrated to have cardiovascular preventive benefits. However, the mechanisms through which LIG protects the cardiovascular and cerebrovascular systems in atherosclerosis (AS) remain unknown. This study was aimed to investigate the mechanisms of LIG in AS utilizing the network pharmacology and molecular docking, and then to validate the putative mechanism through experiments. The network pharmacological analysis indicated that a total of 55 were performed on LIG and AS intersection targets. The genes of LIG and AS intersection targets enriched in the regulation of receptor and enzyme activity, cytokines-related, and transcription factors, indicating that these targets were primarily involved in cell proliferation and migration, regulating cell differentiation and skeletal activities in the development of AS. Finally, molecular docking was used to validate the major targets of LIG and AS intersection targets. Further experiments revealed that LIG may inhibit cell migration induced by AngII by reducing calcium influx, and regulating phenotypic translation-related proteins SM-22α and OPN. The present study investigated the potential targets and signaling pathways of LIG, which provides new insight into its anti-atherosclerosis actions in terms of reducing inflammation, cell proliferation, and migration, and may constitute a novel target for the treatment of AS. PRACTICAL APPLICATIONS: LIG has been shown to have cardiovascular protective benefits, the mechanism by which it protects the cardiovascular and cerebrovascular systems in AS remains unknown. This study uses a holistic network pharmacology strategy to investigate putative treatment pathways and conducts exploratory experimentation. The findings demonstrate that LIG reduces VSMC migration in the treatment of AS, acts as an anti-inflammatory agent, and prevents excessive cell proliferation and migration. Finally, the goal of our research is to uncover the molecular mechanism of LIG's influence on AS. The findings will provide a new research avenue for LIG as well as suggestions for the study of other herbal treatments. These research results will provide a new research direction for LIG and provide guidance for the research of other herbal medicines. This work revealed the multi-component, multi-target, multi-pathway, and multi-dis

Topics: 4-Butyrolactone; Atherosclerosis; Humans; Medicine, Chinese Traditional; Molecular Docking Simulation; Network Pharmacology

Vascular smooth muscle cells (VSMCs) excessive migration, a basic change of pathological intimal thickening, can lead to serious cardiovascular diseases such as atherosclerosis, myocardial infarction, and stroke. Ligustilide (LIG), the main active ingredient of angelica volatile oil, has been demonstrated to exert protective effects on the cardiovascular and cerebrovascular, circulatory system, and immune function. However, whether it protects against intimal thickening and VSMCs excessive migration and its underlying mechanism remains largely unknown. The aim of this study is to investigate the effect of LIG on VSMCs migration and its underlying mechanism. The protective effect of LIG on VSMCs excessive migration was assessed using an atherosclerotic spontaneously hypertensive rat model and an angiotensin II (AngII)-induced VSMCs migration model. The results showed that LIG exerted a protective effect against pathological intimal thickening as demonstrated by decreasing VSMCs migration in vivo and in vitro. In vivo, intimal thickening and VSMCs migration were inhibited and LIG performed a suppressive effect on the expression of c-Myc protein while enhanced phenotypic transformation related proteins α-SMA expression. Meanwhile, the administration of LIG significantly lowered the blood pressure and blood lipids level in atherosclerotic spontaneously hypertensive rats. In vitro, LIG suppressed AngII-induced VSMCs migration and downregulated the expression of migration related protein c-Myc, MMP2, ROCK1, ROCK2, p-JNK, and JNK. These findings suggested the protective effect of LIG on VSMCs migration was associated with the decrement of c-Myc/MMP2 signaling pathway and ROCK-JNK signaling pathway. Thus, LIG may serve as a novel therapeutic agent for preventing cardiovascular disease.

Topics: 4-Butyrolactone; Animals; Atherosclerosis; Blood Pressure; Cell Movement; Cell Proliferation; Cells, Cultured; Humans; Male; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Proto-Oncogene Proteins c-myc; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; rho-Associated Kinases

Oxidative stress-induced endothelial dysfunction is considered to exert a vital role in the development of atherosclerotic coronary heart disease (CHD). NRF2 is a key transcriptional factor against oxidative stress through activation of multiple ARE-mediated genes. Z-Lig is derived from the Ligusticum species with antitumor, anti-inflammation and neuroprotection activities. However, the antioxidant potentials of Z-Lig on endothelial dysfunction and atherosclerosis have not been well elucidated. Therefore, in the present work, we appraise the cytoprotective property and anti-atherosclerosis effect of Z-Lig.. Potential NRF2 activators were screened and verified by luciferase reporter gene assay. The protein and mRNA levels of NRF2 and ARE-mediated genes, and GSH/GSSG level in EA.hy926 cells treated with Z-Lig were detected. The cytoprotective property of Z-Lig was assessed in the tert-butyl hydroperoxide (t-BHP)-evoked oxidative stress model. Cell viability and reactive oxygen species (ROS) levels in EA.hy926 cells were determined. An atherosclerosis model induced by HFD was used to determine the anti-atherosclerosis effect of Z-Lig in HFD-fed Ldlr-deficient mice.. In vitro, 100 μM Z-Lig upregulated expressions of NRF2 and ARE-driven genes, promoted accumulation of nuclear NRF2 and unbound NRF2- KEAP1 complex in EA.hy926 cells. Furthermore, Z-Lig alleviated oxidative stress and cell injury caused by t-BHP via stimulation of the NRF2/ARE pathway. In vivo, intervention with 20 mg/kg Z-Lig markedly restrained atherosclerosis progression, including attenuation of HFD-induced atherosclerotic plaque formation, alleviation of lipid peroxidation and increase in antioxidant enzyme activity in aortas of HFD-fed Ldlr. The present study suggested that Z-Lig is an effective NRF2 activator, which can protect vascular endothelial cells from oxidative stress and rescue HFD-induced atherosclerosis.

Topics: 4-Butyrolactone; Animals; Atherosclerosis; Cells, Cultured; Diet, High-Fat; Endothelial Cells; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidative Stress

Topics: 4-Butyrolactone; Animals; Anti-Inflammatory Agents; Apolipoproteins E; Atherosclerosis; Benzofurans; HEK293 Cells; Humans; Immunologic Factors; Inflammation Mediators; Lipids; Male; Mice, Inbred C57BL; NF-kappa B; Proto-Oncogene Proteins c-akt; Transcription Factor AP-1; Tumor Necrosis Factor Receptor Superfamily, Member 9