Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiovascular disease is the leading cause of morbidity and mortality in westernized populations. Low levels of alpha-tocopherol (AT) are associated with increased incidence of atherosclerosis and increased intakes appear to be protective. Recently, we showed that supplementation with AT resulted in significant decreases in monocyte superoxide anion release, lipid oxidation, interleukin-1 beta (IL-1 beta) release, and adhesion to endothelium. The reduction in superoxide and lipid oxidation by AT seemed to be mediated by inhibition of protein kinase C. The aim of this study was to investigate the mechanism(s) by which AT inhibits IL-1 beta release. Potential mechanisms examined included its effect as an antioxidant and its inhibitory effects on protein kinase C and the cyclooxygenase-lipoxygenase pathways. Although AT decreased superoxide release from activated monocytes, superoxide dismutase and catalase had no effect on IL-1 beta release. Also, a similar antioxidant, beta-tocopherol, had no effect on IL-1 beta release. The protein kinase C inhibitor, bisindolylmaleimide, did not inhibit IL-1 beta release from activated monocytes, in spite of AT decreasing protein kinase C activity. Leukotriene B4, a major product of 5-lipoxygenase, has been shown to augment IL-1beta release. In the presence of AT, a significant reduction in leukotriene B4 and IL-1 beta levels was observed, which was reversed by the addition of leukotriene B4. Similar observations were seen with specific inhibitors of 5-lipoxygenase. The product of cyclooxygenase, prostaglandin E2, has been shown to inhibit IL-1 beta activity in some systems. However, AT had no significant effect on prostaglandin E2 levels in activated monocytes. In the presence of indomethacin, a cyclooxygenase inhibitor, AT inhibited IL-1 beta activity. Also, AT had no effect on IL-1 beta mRNA levels or stability, suggesting a posttranscriptional effect. Thus, in activated human monocytes, AT exerts a novel biological effect of inhibiting the release of the proinflammatory cytokine, IL-1 beta, via inhibition of the 5-lipoxygenase pathway.
 ...
PMID:Alpha-tocopherol decreases interleukin-1 beta release from activated human monocytes by inhibition of 5-lipoxygenase. 1019 45

The development of atherosclerosis is a multifactorial process in which both elevated plasma cholesterol levels and proliferation of smooth muscle cells play a central role. Numerous studies have suggested the involvement of oxidative processes in the pathogenesis of atherosclerosis and especially of oxidised low density lipoproteins. Some epidemiological studies have shown an association between high dietary intake or high serum concentrations of vitamin E and lower rates of ischemic heart disease. Recently, the Cambridge Heart Antioxidant Study (CHAOS) reported strong protection by high vitamin E doses against the risk of fatal and non fatal myocardial infarction. Here we have shown that incubation of vascular smooth muscle cells in the presence of alpha-tocopherol resulted in inhibition of cell proliferation and protein kinase C activity. Since beta-tocopherol and probucol are not inhibitory, the effect of alpha-tocopherol is considered due to a non-oxidant mechanism. In order to understand the protective role of alpha-tocopherol against atherosclerosis in vivo the following rabbit studies were carried out. Atherosclerosis was induced by a vitamin E poor diet containing 2% cholesterol in a group of rabbit. The other groups had 2% cholesterol in the diet plus 50 mg/kg vitamin E i.m. or 1% probucol or 50 mg/kg vitamin E plus 1% probucol. After 4 weeks, aortas were removed and analysed by microscopy for atherosclerotic lesions. Samples of the media were analysed for protein kinase C activity. The aortas of cholesterol-fed rabbits showed typical atherosclerotic lesions, detected by microscopic examination, their media smooth muscle cells exhibited an increase in protein kinase C activity. Vitamin E fully prevented cholesterol induced atherosclerotic lesions and the induction of protein kinase C activity while probucol was not effective. These results show that the protective effect of vitamin E against hypercholesterolemic atherosclerosis is not produced by an other antioxidant such as probucol and, therefore, may not be linked to the antioxidant properties of this vitamin. The effects observed at the level of smooth muscle cells in vitro and ex-vivo suggests an involvement of signal transduction events in the protective effect of vitamin E against atherosclerosis.
 ...
PMID:Effect of vitamin E on the development of atherosclerosis. 1096 37

Inflammatory and immune responses are highly relevant processes in the pathogenesis of atherosclerosis, as illustrated by the central event of monocyte accumulation in atherosclerotic plaques. Integrin LFA-1-mediated adhesion of circulating monocytes to the endothelium is a prerequisite for recruitment of monocytes to these areas. Integrin-mediated adhesion is tightly regulated and integrins are only functional in response to particular monocyte activation stimuli. We investigated the role of oxidized low-density lipoprotein (LDL) in adhesion of resting monocytes prepared by elutriation from endothelium. Our results showed that: (1) oxidized LDL (and MCP-1) induced both LFA-1-mediated adhesion of monocytes to endothelial cells and transendothelial migration of monocytes; (2) oxidized LDL functionally transformed monocyte LFA-1 to an activated form; (3) oxidized LDL induced F-actin polymerization and cytoskeletal rearrangement within seconds; and (4) the LDL-associated antioxidant, alpha-tocopherol, but not beta-tocopherol, inhibited both F-actin polymerization and LFA-1-mediated adhesion of monocytes, which paralleled the effect of protein kinase C (PKC) inhibitors. Our results indicate that oxidized LDL plays a pivotal role in triggering LFA-1 activation and LFA-1-mediated adhesion and transmigration of monocytes to sites of atherosclerotic plaques, via the PKC pathway.
Atherosclerosis 2002 Feb
PMID:Oxidized low density lipoprotein-induced LFA-1-dependent adhesion and transendothelial migration of monocytes via the protein kinase C pathway. 1184 49

The effect of alpha-tocopherol treatment on gene expression in human aortic vascular smooth muscle cells was analyzed by gene expression arrays. The expression of the connective tissue growth factor (CTGF) gene was induced by alpha-tocopherol 1.8-fold in gene array experiments, and similar results were also obtained by RT-PCR (1.7-fold) and at the protein level (1.4-fold). The antioxidants beta-tocopherol and N-acetylcysteine did not induce CTGF gene expression, suggesting a nonantioxidant mechanism for alpha-tocopherol action. Protein kinase C (PKC) inhibition by alpha-tocopherol has been previously described. However, PKC downregulation did not prevent CTGF induction by alpha-tocopherol, and inhibition of PKC activity with several inhibitors did not increase its expression, suggesting an alternative pathway for the alpha-tocopherol effect. On the other hand, tumor necrosis factor-alpha reduced the expression of CTGF, an effect that was reversed by antioxidants. The data suggest that tumor necrosis factor-alpha inhibition of CTGF gene expression is prevented in an antioxidant-sensitive process and that alpha-tocopherol increases CTGF expression by a PKC-independent, nonantioxidant mechanism. Because CTGF stimulates the synthesis of extracellular matrix, the normalization of CTGF gene expression by alpha-tocopherol may accelerate wound repair and tissue regeneration during atherosclerosis.
 ...
PMID:Alpha-tocopherol induces expression of connective tissue growth factor and antagonizes tumor necrosis factor-alpha-mediated downregulation in human smooth muscle cells. 1252 27

Anti-angiogenic therapy reduces both plaque growth and intimal neovascularization in apolipoprotein-E-deficient mice (apoE-/-). Vascular endothelial growth factor (VEGF) has been suggested as playing a role in the development of atherosclerosis. We examined the hypothesis that VEGF and VEGF receptor-2 (VEGFR-2) expression is upregulated in apoE-/- and, since it could be driven by oxidative stress, tested whether dietary supplementation with vitamins C and E could downregulate it.Two-month-old apoE-/- received vitamin C combined with alpha- or beta-tocopherol for 4 weeks. Aortic VEGF and VEGFR-2 expression were measured by RT-qPCR and western blot.ApoE-/- showed significantly higher expression of aortic VEGF and VEGFR-2 mRNA (P<0.001) and protein (P<0.001) than wild-type mice, as well as increased plasma VEGF (P<0.001). Vitamin C and alpha-tocopherol significantly reduced aortic VEGF and VEGFR-2 expression in apoE-/- (P<0.001), circulating VEGF (P<0.01) and plasma lipid peroxidation (P<0.01). apoE-/- receiving vitamin C and beta-tocopherol showed diminished lipid peroxidation and VEGFR-2, but only partial reduction of VEGF expression. These data demonstrate that augmented VEGF and VEGFR-2 expression in apoE-/- vasculature can be downregulated by vitamins C and E, at least partially through oxidative stress reduction. This novel mechanism could contribute to explaining the beneficial effects of antioxidant vitamins in experimental atherosclerosis.
Atherosclerosis 2003 Nov
PMID:Vitamins C and E downregulate vascular VEGF and VEGFR-2 expression in apolipoprotein-E-deficient mice. 1464 7