Cellular Metabolomics Reveal the Mechanism Underlying the Anti-Atherosclerotic Effects of Aspirin Eugenol Ester on Vascular Endothelial Dysfunction

Abstract

Aspirin eugenol ester (AEE) possesses anti-thrombotic, anti-atherosclerotic and anti-oxidative effects. The study aims to clarify the mechanism underlying the anti-atherosclerotic effects of AEE on vascular endothelial dysfunction. Both the high-fat diet (HFD)-induced atherosclerotic rat model and the H2O2-induced human umbilical vein endothelial cells (HUVECs) model were used to investigate the effects of AEE on vascular endothelial dysfunction. UPLC/QTOF-MS coupled with a multivariate data analysis method were used to profile the variations in the metabolites of HUVECs in response to different treatments. Pretreatment of HUVECs with AEE significantly ameliorated H2O2-induced apoptosis, the overexpression of E-selectin and VCAM-1, and the adhesion of THP-1 cells. Putative endogenous biomarkers associated with the inhibition of endothelial dysfunction were identified in HUVECs pretreated with AEE in the absence or presence of H2O2, and these biomarkers were involved in important metabolic pathways, including amino acid metabolism, carbohydrate metabolism, and glutathione metabolism. Moreover, in vivo, AEE also significantly reduced vascular endothelial dysfunction and decreased the overexpression of VCAM-1 and E-selectin. Based on our findings, the mechanism underlying the anti-atherosclerotic effects of AEE might be related to a reduction in vascular endothelial dysfunction mediated by ameliorating alterations in metabolism, inhibiting oxidative stress, and decreasing the expression of adhesion molecules.

Dietary Ethanolic Extract of Mangosteen pericarp Reduces VCAM-1, Perivascular Adipose Tissue and Aortic Intimal Medial Thickness in Hypercholesterolemic Rat Model

“…Increased expression of VCAM-1 in HFD group showed a positive tendency. This result is accordance with previous research by Huang et al, reported that after treating rats with HFD for 12 weeks, VCAM-1 expression in the aorta and the levels of sVCAM-1 were increased significantly [23]. After EEMP administration, VCAM-1 expression displayed a significant decrease.…”

Metabolomic Approaches to Study Chemical Exposure-Related Metabolism Alterations in Mammalian Cell Cultures

“…However, the quantitative measurement of exometabolites in supernatants after cell culture, and comparison to control media not put in contact with cells, allows the determination of consumption and secretion rates per unit of time that convey rich insights over cellular metabolism. Indeed, exometabolites rates are excellent reporters of the cell physiology that allow for the predicting of the intracellular metabolic state and evidence mechanisms of chemical-induced metabolic reprogramming [ 20 , 144 ]. For example, glucose consumption and lactate/pyruvate secretion rates are simple to determine yet powerful indicators of the glycolytic activity in cells [ 47 ], and the extracellular secretion of citrate and succinate evidence mitochondrial metabolism remodeling.…”

“…Metabolic modeling exploits multiple facets of metabolomics approaches for the characterization of whole organisms, their pathologies, and adaptations to changeable environmental conditions. Metabolomic analyses of body fluids refer to systemic overviews of an organism’s state, however concealing important information about the behavior of cells that underlie changes in the dynamic homeostasis at the organism level [ 9 , 20 ]. Modeling cellular metabolism allows one to investigate biological processes but also serves a predictive role for verifying diagnostic hypotheses using cell cultures in vitro.…”

“…The benefits of using cell culture models in metabolomics studies are multiple and include low experimental costs and high data reproducibility. They allow the determination of metabolite biomarkers that characterize physiological and pathological states of the cell and importantly provide data easier to interpret than those obtained in animal models or human biofluids [ 20 ]. Cell culture also offers a large panel of options regarding the choice of tissue-specific derived cells, allowing to target cell-type-specific responses [ 12 ].…”

The Protective Effect of Aspirin Eugenol Ester on Oxidative Stress to PC12 Cells Stimulated with H2O2 through Regulating PI3K/Akt Signal Pathway

“…As a new compound, AEE plays an active role in many aspects [31][32][33][34][35][36][37][38][39][40]. AEE can prevent tail thrombosis induced by kappa-carrageenan in rats [39].…”