benzofurans and Atherosclerosis

According to the oxidative modification hypothesis, antioxidants that inhibit the oxidation of low-density lipoprotein (LDL) are expected to attenuate atherosclerosis, yet not all antioxidants that inhibit LDL oxidation in vitro inhibit disease in animal models of atherosclerosis. As with animal studies, a benefit with dietary supplements of antioxidants in general and vitamin E in particular was anticipated in humans, yet the overall outcome of large, randomized controlled studies has been disappointing. However, in recent years it has become clear that the role of vitamin E in LDL oxidation and the relationship between in vitro and in vivo inhibition of LDL oxidation are more complex than previously appreciated, and that oxidative events in addition to LDL oxidation in the extracellular space need to be considered in the context of an antioxidant as a therapeutic drug against atherosclerosis. This review focuses on some of these complexities, proposes a novel method to assess in vitro 'oxidizability' of lipoprotein lipids, and summarizes the present situation of development of antioxidant compounds as drugs against atherosclerosis and related cardiovascular disorders.

Topics: Animals; Antioxidants; Atherosclerosis; Benzofurans; Cardiovascular Diseases; Humans; Lipoproteins, LDL; Malondialdehyde; Oxidation-Reduction; Probucol; Thiobarbituric Acid Reactive Substances

Salvianolic acid B (SalB) is effective for treating cardiovascular diseases. However, the molecular mechanisms underlying its therapeutic effects remain unclear. Mechanosensitive Piezo1 channels play important roles in vascular biology, although their pharmacological properties are poorly defined. Here, we aimed to identify novel Piezo1 inhibitors and gain insights into their mechanisms of action.. Intracellular Ca. Salvianolic acid B inhibited Yoda1-induced Ca. Our study provides novel mechanistic insights into the inhibitory role of salvianolic acid B against Piezo1 channels and improves our understanding of salvianolic acid B in preventing atherosclerotic lesions.

Topics: Animals; Atherosclerosis; Benzofurans; Endothelial Cells; Ion Channels; Mice; RAW 264.7 Cells

Topics: Animals; Atherosclerosis; Benzofurans; Brain Ischemia; Endothelial Cells; Mice; Neuroprotective Agents; Oxidative Stress; Rats; Stroke

Atherosclerosis (AS) is the greatest contributor to pathogenesis of atherosclerotic cardiovascular disease (ASCVD), which is associated with increased mortality and reduced quality of life. Early intervention to mitigate AS is key to prevention of ASCVD. Salvianolic acid B (Sal B) is mainly extracted from root and rhizome of Salvia Miltiorrhiza Bunge, and exerts anti-atherosclerotic effect. The purpose of this study was to screen for anti-AS targets of Sal B and to characterize immune cell infiltration in AS.. We identified targets of Sal B using SEA ( http://sea.bkslab.org/ ) and SIB ( https://www.sib.swiss/ ) databases. GSE28829 and GSE43292 datasets were obtained from Gene Expression Omnibus database. We identified differentially expressed genes (DEGs) and performed enrichment analysis. Weighted gene co-expression network analysis (WGCNA) was used to determine the most relevant module associated with atherosclerotic plaque stability. Intersecting candidate genes were evaluated by generating receiver operating characteristic (ROC) curves and molecular docking. Then, immune cell types were identified using CIBERSOFT and single-sample gene set enrichment analysis (ssGSEA), the relationship between candidate genes and immune cell infiltration was evaluated. Finally, a network-based approach to explore the candidate genes relationship with microRNAs (miRNAs) and Transcription factors (TFs).. MMP9 and MMP12 were been selected as candidate genes from 64 Sal B-related genes, 81 DEGs and turquoise module with 220 genes. ROC curve results showed that MMP9 (AUC = 0.815, P<0.001) and MMP12 (AUC = 0.763, P<0.001) were positively associated with advanced atherosclerotic plaques. The results of immune infiltration showed that B cells naive, B cells memory, Plasma cells, T cells CD8, T cells CD4 memory resting, T cells CD4 memory activated, T cells regulatory (Tregs), T cells gamma delta, NK cells activated, Monocytes, and Macrophages M0 may be involved in development of AS, and the candidate genes MMP9 and MMP12 were associated with these immune cells to different degrees. What' s more, miR-34a-5p and FOXC1, JUN maybe the most important miRNA and TFs.. The anti-AS effects of Sal B may be related to MMP9 and MMP12 and associated with immune cell infiltration, which is expected to be used in the early intervention of AS.

Topics: Atherosclerosis; Benzofurans; Computational Biology; Gene Expression Profiling; Gene Regulatory Networks; Humans; Matrix Metalloproteinase 12; Matrix Metalloproteinase 9; MicroRNAs; Molecular Docking Simulation; Plaque, Atherosclerotic; Protein Interaction Maps; Quality of Life

Vascular endothelial cells and oxidation reduction system play an important role in the pathogenesis of atherosclerosis (AS). If these conditions are disordered, it will inevitably lead to plaque formation and even rupture. Astragaloside IV (AsIV) and salvianolic acid B (Sal B) are the main active ingredients of Astragalus membranaceus and Salvia miltiorrhiza, respectively, and found to ameliorate vascular endothelial dysfunction and protect against oxidative stress in recent studies. However, it is still unknown if the combination of AsIV and Sal B (AsIV + Sal B) can inhibit the development of plaque through amplifying the protective effect of vascular endothelial cells and anti-oxidative stress effect. To clarify the role of AsIV + Sal B in AS, we observed the efficacy of each group (Control, Model, AsIV, Sal B, and AsIV + Sal B) by biomolecular assays, such as observing the pathological morphology of the aorta by oil red O staining, evaluating the level of oxidative stress and endothelial cells in the serum by the Elisa test, and analyzing the changes of all small molecule metabolites in liver tissue by UPLC-QTOF-MS. Results showed that AsIV, Sal B and AsIV + Sal B decreased the deposition of lipid in the arterial wall, so as to exert the effect of anti-oxidant stress and vascular endothelial protection, where the inhibitory effect of AsIV + Sal B was the most obvious. Metabonomics analysis showed that Sal B regulated the metabolic pathways of arginine and proline. AsIV regulated glycerol metabolism and saturated fatty acid biosynthesis metabolism. AsIV + Sal B is mainly related to the regulation of the citrate cycle (TCA cycle), alanine, aspartic acid, and glutamate metabolism, cysteine, and methionine metabolism. Succinic acid and methionine are synergistic metabolites that exert an enhancing effect when AsIV and Sal B were used in combination. In conclusion, we demonstrated that AsIV acompanied with Sal B can be successfully used for anti-oxidative stress and vascular endothelial protection of AS, and succinic acid and methionine are the synergistic metabolites.

Topics: Antioxidants; Atherosclerosis; Benzofurans; Endothelial Cells; Humans; Methionine; Saponins; Succinic Acid; Triterpenes

Progressive macrophage dysfunction and apoptosis are some of the major events that occur during atherogenesis. To further investigate the intrinsic association between atherosclerosis (AS) and macrophage apoptosis and autophagy, cholesterol crystals (CHCs) were used to stimulate RAW264.7 macrophages to establish a macrophage model of advanced AS. Cells in the CHC group were treated with salvianolic acid B (Sal B) to evaluate its protective effects and reveal its underlying molecular mechanism. The results demonstrated that treatments with Sal B significantly improved autophagy dysfunction and reduced the apoptotic rate of CHC‑induced macrophages. Furthermore, Sal B significantly attenuated CHC‑induced release of proinflammatory factors (TNF‑α and IL‑6) by macrophages. Treatment of macrophages with a specific inhibitor of autophagy (3‑methyladenine) significantly reversed Sal B‑mediated effects on autophagy, suggesting that Sal B‑induced autophagy may display a protective effect in CHC‑induced macrophages. Furthermore, pretreatment of CHC‑induced macrophages with insulin significantly decreased Sal B‑induced autophagy, indicating that the Akt/mTOR signaling pathway may serve as a critical mediator in regulating Sal B‑mediated cell death. Taken together, the present study demonstrated that Sal B improved autophagic dysfunction and reduced the apoptosis of CHC‑induced macrophages via inhibiting the Akt/mTOR signaling pathway.

Topics: Animals; Apoptosis; Atherosclerosis; Autophagy; Benzofurans; Drugs, Chinese Herbal; Macrophages; Mice; Protective Agents; Proto-Oncogene Proteins c-akt; RAW 264.7 Cells; Salvia miltiorrhiza; TOR Serine-Threonine Kinases

Red wine compounds have been reported to reduce the rate of atherosclerosis by inducing nitric oxide (NO) production and antioxidant enzyme expression in vascular endothelial cells (VECs). The present study compared the effects of the three red wine compounds resveratrol and its dimers, ε-viniferin and δ-viniferin, on VECs function for the first time. Both 5 μM ε-viniferin and δ-viniferin, but not 5 μM resveratrol, significantly stimulated wound repair of VECs. Increased levels of wound repair induced by 10 and 20 μM ε-viniferin were significantly higher than those stimulated by 10 and 20 μM resveratrol, respectively. These stimulatory effects of the three compounds were suppressed by the NO synthase inhibitor L-NAME. When VECs were exposed to each compound, endothelial NO synthase was activated and the expression of sirtuin 1 (SIRT1) and HO-1 was induced. Addition of the SIRT1 and HO-1 inhibitors EX527 and ZnPPiX, respectively, suppressed wound repair stimulated by the three compounds, demonstrating that SIRT1 and HO-1 are involved in these wound repair processes. Furthermore, each compound induced the suppression of H

Topics: Animals; Antioxidants; Atherosclerosis; Benzofurans; Carbazoles; Catalase; Cell Line; Cell Survival; Dimerization; Endothelial Cells; Enzyme Inhibitors; Gene Expression Regulation; Heme Oxygenase-1; Humans; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type III; Protoporphyrins; Resorcinols; Resveratrol; Sirtuin 1; Stilbenes; Swine; Wine

Topics: Acyltransferases; Adaptor Proteins, Signal Transducing; Animals; Apolipoproteins E; Atherosclerosis; Benzofurans; Cell Survival; Endothelial Cells; Gene Expression Regulation; Humans; MAP Kinase Kinase 4; MAP Kinase Signaling System; Mice; Pericytes; Transcription Factors; YAP-Signaling Proteins

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

Inflammation plays a crucial role in the pathophysiology of atherosclerosis. Besides cytokines, chemokines and cell adhesion molecules, CD40 and P-selectin play important roles as key regulators of the inflammatory process in atherosclerosis. Danshen (DS) is commonly used in traditional Chinese medicine for therapy of cardiovascular diseases such as coronary artery disease. The aim of the present study was to evaluate the protective effects of DS with respect to possible anti-inflammatory effects. Human umbilical vein endothelial cells as well as platelets were incubated with an extract of DS or one of its major ingredients salvianolic acid B (Sal B), tanshinone IIA (Tansh) and protocatechuic acid (Protoc) under tumor necrosis factor (TNF)-α or ADP stimulation. Expression of CD40 and cellular adhesion molecules (VCAM-1/ICAM-1) were assessed via flow cytometry. Levels of interleukin (IL)-6, IL-8, monocyte-chemoattractant-protein (MCP)-1 as well as soluble VCAM1 and ICAM-1 in the supernatants were examined via luminex based analysis. Treatment with DS attenuated TNF-α induced expression of CD40. Furthermore, the expression of VCAM-1 and ICAM-1 as well as the release of soluble VCAM-1 and ICAM-1 were downregulated. In the cell supernatants we also observed a significant reduction of IL-6, IL8 and MCP-1. DS and its major ingredients, Sal B and Protoc, significantly inhibited TNF-induced expression and release of adhesion molecules, cytokines and chemokines as well as ADP-induced expression of platelet P-selectin. Because of the key roles of inflammatory mediators in the etiology of atherosclerosis, this work provides useful insight in understanding the pharmacological efficacy of Chinese herbal medicine.

Topics: Abietanes; Adenosine Diphosphate; Anti-Inflammatory Agents; Atherosclerosis; Benzofurans; Blood Platelets; CD40 Antigens; Cells, Cultured; Chemokine CCL2; Down-Regulation; Drugs, Chinese Herbal; Human Umbilical Vein Endothelial Cells; Humans; Hydroxybenzoates; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; P-Selectin; Salvia miltiorrhiza; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

CD36, a class B scavenger receptor, has been implicated in the pathogenesis of a host of vascular inflammatory diseases. Through a high-throughput screening (HTS) assay for CD36 antagonist, we previously identified salvianolic acid B (SAB), a hydrophilic component derived from the herb Danshen, as a potential candidate. Danshen, the dried roots of Salvia miltiorrhiza, has been widely used in China for the prevention and treatment of atherosclerosis-related disorders. Previous studies showed that SAB acted as an anti-oxidant by preventing lipid peroxidation and oxidized LDL (oxLDL) formation. The present study was to investigate the specificity and efficacy of SAB in the inhibition of CD36-mediated lipid uptake. SAB reduced modified LDL (mLDL) uptake in a dose-dependent manner in phorbol-12-myristate-13-acetate (PMA)-stimulated THP-1 and RAW 264.7 cells. In the CD36 silenced THP-1 cells, SAB had no effect in reducing mLDL uptake, whereas its overexpression in CHO cells reinstates the effect, indicating a specific involvement of SAB in antagonizing the CD36's function. Surface plasmon resonance (SPR) analysis revealed a direct binding of SAB to CD36 with a high affinity (K(D) = 3.74 μM), confirming physical interactions of SAB with the receptor. Additionally, SAB reduced oxLDL-induced CD36 gene expression in the cultured cell lines and primary macrophages. In ApoE KO mice fed a high fat diet, SAB reduced CD36 gene expression and lipid uptake in macrophages, showing its ability to antagonize CD36 pathways in vivo. These results demonstrate that SAB is an effective CD36 antagonist and suggest SAB as a potential anti-atherosclerotic agent.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Benzofurans; Biological Transport; CD36 Antigens; Cell Line, Tumor; CHO Cells; Cricetinae; Cricetulus; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipoproteins, LDL; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, LDL; RNA Interference; Surface Plasmon Resonance; Tetradecanoylphorbol Acetate; Time Factors; Transfection

We previously reported that in healthy mouse cerebral arteries, endothelial nitric oxide synthase (eNOS) produces H₂O₂, leading to endothelium-dependent dilation. In contrast, thromboxane A₂ (TXA₂), a potent pro-oxidant and pro-inflammatory endogenous vasoconstrictor, is associated with eNOS dysfunction. Our objectives were to elucidate whether (1) the cerebrovascular eNOS-H₂O₂ pathway was sensitive to oxidative stress associated with aging and dyslipidemia and (2) TXA₂ contributed to cerebral eNOS dysfunction. Atherosclerotic (ATX = LDLR(-/-); hApoB(+/+)) and wild-type (WT) control mice were used at 3 and 12 months old (m/o). Three-m/o ATX mice were treated with the cardio-protective polyphenol catechin for 9 months. Dilations to ACh and the simultaneous eNOS-derived H₂O₂ production were recorded in isolated pressurized cerebral arteries. The age-associated decrease in cerebral eNOS-H₂O₂ pathway observed in WT was premature in ATX mice, decreasing at 3 m/o and abolished at 12 m/o. Thromboxane synthase inhibition by furegrelate increased dilations at 12 months in WT and at 3 and 12 months in ATX mice, suggesting an anti-dilatory role of TXA₂ with age hastened by dyslipidemia. In addition, the non-selective NADP(H) oxidase inhibitor apocynin improved the eNOS-H₂O₂ pathway only in 12-m/o ATX mice. Catechin normalized the function of this pathway, which became sensitive to L-NNA and insensitive to furegrelate or apocynin; catechin also prevented the rise in TXA₂ synthase expression. In conclusion, the age-dependent cerebral endothelial dysfunction is precocious in dyslipidemia and involves TXA₂ production that limits eNOS activity. Preventive catechin treatment reduced the impact of endogenous TXA₂ on the control of cerebral tone and maintained eNOS function.

Topics: Acetophenones; Aging; Animals; Antioxidants; Atherosclerosis; Benzofurans; Catechin; Cerebral Arteries; Enzyme Inhibitors; Hemodynamics; Humans; Hydrogen Peroxide; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type III; Oxidants; Oxidative Stress; Receptors, LDL; Thromboxane A2; Thromboxane-A Synthase; Up-Regulation

Resveratrol is a strong candidate for explaining an irreversible correlation between red wine consumption and coronary heart disease. The present study examined the effect of ε-viniferin, a dehydrodimer of resveratrol, on vascular smooth muscle cells (VSMCs), because ε-viniferin functions are poorly understood in spite of its comparable content to resveratrol in red wines and grapes. Both ε-viniferin and resveratrol inhibited platelet-derived growth factor-induced cell proliferation, migration, and reactive oxygen species (ROS) production, in addition to inducing nitric oxide generation. ε-Viniferin was more effective than resveratrol in these effects, except for inhibiting ROS production. The compounds also increased the expression of the antioxidant enzyme, hemeoxygenase-1, via transcription factor Nrf2. The phosphatidylinositol 3-kinase-Akt pathway was implicated in resveratrol-dependent nuclear Nrf2 accumulation, whereas extracellular signal-regulated kinase and p38 were involved in ε-viniferin-induced Nrf2 accumulation. These data suggest that ε-viniferin may function more effectively than resveratrol in different mechanisms and cooperatively with resveratrol in preventing atherosclerosis.

Topics: Animals; Atherosclerosis; Benzofurans; Cell Movement; Cell Proliferation; Cells, Cultured; Extracellular Signal-Regulated MAP Kinases; Heme Oxygenase-1; Mitogen-Activated Protein Kinases; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nitric Oxide; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Resveratrol; Stilbenes; Wine

Ample evidence supports the critical role of oxidized low-density lipoprotein (ox-LDL) in initiation and progression of atherosclerosis. Oxidation of LDL is a complex process involving several steps (processes) of reactions such as initiation and propagation. Both proteins and lipids in LDL undergo free radical-mediated oxidations leading to the formation of ox-LDL that plays a pivotal role in atherosclerosis. Antioxidants of various types (both aqueous and lipophilic) either arrest or retard the oxidation of LDL at various steps of the oxidation process (e.g., initiation or propagation). Certain lipophilic antioxidants act as the chain-terminating antioxidants leading to the inhibition of LDL oxidation. The current chapter describes the designing and efficacy of two novel lipophilic antioxidants (benzofuranol, BO-653 and aniline, BO-313) in inhibiting the LDL oxidation and atherogenesis in experimental animal model. Furthermore, the characteristics of an effective antioxidant to inhibit LDL oxidation and atherogenesis which dictates the designing of the antioxidant drug and its mechanism(s) of antiatherogenic action are discussed.

Topics: Aniline Compounds; Animals; Antioxidants; Atherosclerosis; Benzofurans; Copper; Disease Models, Animal; Drug Design; Female; Lipoproteins, LDL; Male; Molecular Structure; Oxidation-Reduction; Rabbits; Thiobarbituric Acid Reactive Substances

Using Triton WR-1339-induced hyperlipidemic rats as an experimental model, we investigated whether compound 4 [N-(9,10-dihydro-9,10-dioxoanthracen-2-yl)benzofuran-2-carboxamide] and compound 5 [N-(4-benzoylphenyl)benzofuran-2-carboxamide], two novel anti-hyperlipidemic agents, have any effect on plasma triglyceride (TG), total cholesterol (TC), and high-density lipoprotein cholesterol levels (HDL-C) levels. The tested animals were divided into control (CG), hyperlipidemic (HG), and compounds 4, 5, and bezafibrate (BF) treated groups. At a dose of 15 mg/kg body weight, compounds 4, 5, and BF significantly reduced elevated plasma TG levels after 7 and 24 h. Furthermore, HDL-C levels were remarkably increased in all treated groups after 7 and 24 h compared to the hyperlipidemic control group. However, only compounds 4 and 5 treated groups clearly showed a significant reduction in plasma total cholesterol levels after 7 and 24 h. It is therefore reasonable to assume that compounds 4 and 5 may have promising potential in the treatment of hyperlipidemia and atherosclerosis.

Topics: Animals; Anthracenes; Atherosclerosis; Benzofurans; Bezafibrate; Cholesterol; Cholesterol, HDL; Detergents; Drug Design; Hyperlipidemias; Hypolipidemic Agents; Lipids; Male; Molecular Structure; Polyethylene Glycols; Random Allocation; Rats; Rats, Wistar; Time Factors; Triglycerides

Cyclooxygenase (COX)-2 is among the endothelial genes upregulated by uniform laminar shear stress (LSS), characteristically associated with atherosclerotic lesion-protected areas. We have addressed whether the induction of COX-2-dependent prostanoids in endothelial cells by LSS plays a role in restraining endothelial tumor necrosis factor (TNF)-alpha generation, a proatherogenic cytokine, through the induction of heme oxygenase-1 (HO)-1, an antioxidant enzyme. In human umbilical vein endothelial cells (HUVECs) exposed to steady LSS of 10 dyn/cm(2) for 6 hours, COX-2 protein was significantly induced, whereas COX-1 and the downstream synthases were not significantly modulated. This was associated with significant (P<0.05) increase of 6-keto-prostaglandin (PG)F(1alpha) (the hydrolysis product of prostacyclin), PGE(2), and PGD(2). In contrast, TNF-alpha released in the medium in 6 hours (3633+/-882 pg) or detected in cells lysates (1091+/-270 pg) was significantly (P<0.05) reduced versus static condition (9100+/-2158 and 2208+/-300 pg, respectively). Coincident induction of HO-1 was detected. The finding that LSS-dependent reduction of TNF-alpha generation and HO-1 induction were abrogated by the selective inhibitor of COX-2 NS-398, the nonselective COX inhibitor aspirin, or the specific prostacyclin receptor (IP) antagonist RO3244794 illuminates the central role played by LSS-induced COX-2-dependent prostacyclin in restraining endothelial inflammation. Carbacyclin, an agonist of IP, induced HO-1. Similarly to inhibition of prostacyclin biosynthesis or activity, the novel imidazole-based HO-1 inhibitor QC15 reversed TNF-alpha reduction by LSS. These findings suggest that inhibition of COX-2-dependent prostacyclin might contribute to acceleration of atherogenesis in patients taking traditional nonsteroidal antiinflammatory drugs (NSAIDs) and NSAIDs selective for COX-2 through downregulation of HO-1, which halts TNF-alpha generation in human endothelial cells.

Topics: 6-Ketoprostaglandin F1 alpha; Aspirin; Atherosclerosis; Benzofurans; Cells, Cultured; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Down-Regulation; Endothelial Cells; Epoprostenol; Heme Oxygenase-1; Humans; Inflammation; Nitrobenzenes; Perfusion; Propionates; Prostaglandin D2; Receptors, Epoprostenol; Receptors, Prostaglandin; Stress, Mechanical; Sulfonamides; Tumor Necrosis Factor-alpha; Up-Regulation

Vitamin E has failed to protect humans from cardiovascular disease outcome, yet its role in experimental atherosclerosis remains less clear. A previous study (Proc. Natl. Acad. Sci. USA 97:13830-13834; 2000) showed that vitamin E deficiency caused by disruption of the alpha-tocopherol transfer protein gene (Ttpa) is associated with a modest increase in atherosclerosis in apolipoprotein E gene deficient (Apoe(-/-)) mice. Here we confirm this finding and report that in Apoe(-/-)Ttpa(-/-) mice dietary alpha-tocopherol (alphaT) supplements restored circulating and aortic levels of alphaT, and decreased atherosclerosis in the aortic root to a level comparable to that seen in Apoe(-/-) mice. However, such dietary supplements did not decrease disease in Apoe(-/-) mice, whereas dietary supplements with a synthetic vitamin E analog (BO-653), either alone or in combination with alphaT, decreased atherosclerosis in Apoe(-/-) and in Apoe(-/-)Ttpa(-/-) mice. Differences in atherosclerosis were not associated with changes in the arterial concentrations of F(2)-isoprostanes and cholesterylester hydro(pero)xides, nor were they reflected in the resistance of plasma lipids to ex vivo oxidation. These results show that vitamin E at best has a modest effect on experimental atherosclerosis in hyperlipidemic mice, and only in situations of severe vitamin E deficiency and independent of lipid oxidation in the vessel wall.

Topics: alpha-Tocopherol; Animals; Apolipoproteins E; Atherosclerosis; Benzofurans; Dietary Supplements; Lipid Peroxidation; Lipoproteins; Male; Mice; Mice, Transgenic; Oxidative Stress; Oxygen; Ubiquinone; Vitamin E; Vitamin E Deficiency