Systematic understanding the mechanisms of Tripterygium wilfordii on atherosclerosis and pharmacodynamics research in Apo E-/-mice model

Abstract

Background: Atherosclerosis (AS) is a chronic arterial disease and a major cause of vascular death, with multiple pathogenesis including chronic inflammatory. Tripterygium wilfordii (TGW) had a good effect on an anti-inflammatory. At present, more and more researches indicated that TGW could also regulate AS. Objective: The aim of this study is to clarify what the anti-atherosclerotic ingredients are in TGW and whether these ingredients improve AS synergistically. Materials and Methods: First, systematic pharmacology was utilized to predict the active ingredients and potential targets of TGW related to AS. Then, a bioactive compound of triptolide (TPL) and Tripterine (TPR) in TGW were evaluated if they presented the synergistically anti-atherosclerotic effects in Apo E-/-mice fed with a high-fat/high-cholesterol diet. In the experiment, Hematoxylin and Eosin tested the plaque areas; reverse transcriptase- polymerase chain reaction and Western blot analysis detected the matrix metalloprotein 9 (MMP-9), tumor necrosis factor alpha (TNF-α), and NF-κB levels in the aortas. Results: The results shown that there are 17 bioactive compounds with 76 therapeutic proteins were identified. Moreover, TGW exhibits a protective effect on treatment AS likely through regulating multiple pathways including immune response, inflammatory response, and vascular structure improving. Further verified that TPL combined with TPR in TGW had synergistic effect on treatment AS by reducing levels of MMP-9, TNF-α, and NF-κB, might be the important pathway. Conclusion: TGW, synergistic effect of different compounds, could regulate AS by multiple pathways, especially improving immune response, inflammatory response, and vascular structure. The major compounds of Tripterine and Triptolide in TGW had a synergistic effect on anti-AS by suppressing matrix metalloprotein 9, TNF-α, and NF-κB. Abbreviations used: TGW: Tripterygium wilfordii, TRL: Triptolide, TRR: Tripterine, TRLR: TRL plus TRR, NC: Normal control, MC: Model control, MMP-9: Matrix metalloprotein 9; NF-kB, Nuclear factor-kappa B; TNF-a, Tumor necrosis factor alpha, AS: Atherosclerosis, H and E: Hematoxylin and Eosin, ox-LDL: Oxidized low-density lipoprotein, ICAM-1: intercellular adhesion molecule-1, VCAM-1: vascular cell adhesion molecule 1, HIF-1: Hypoxia inducible factor-1, IL-2: Interleukin-2, IFN-γ: Interferon-γ, MCP-1: Monocyte chemotactic protein 1, TCMSP: Traditional chinese medicine systems pharmacology, TCM: Traditional chinese medicine, PerOB: Predict oral bioavailability, PerDL: Predict drug-likeness, HL: Half-life, HFC: High-fat/high-cholesterol diet, T-P: Target-Pathway, KEGG: Kyoto Encyclopedia of Genes and Genomes, DAVID: Database for Annotation, Visualization and Integrated Discovery, ADME: Absorption, distribution, metabolism, excretion, TBST: tris-buffered saline, GAPDH: Glyceraldehyde-3-phosphate dehydrogenase, DMSO: Dimethyl sulfoxide, HPLC: High Performance Liquid Chromatography.