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

So-called coplanar polychlorinated biphenyls (PCBs), as well as other environmental contaminants that are aryl hydrocarbon receptor (AhR) agonists, may compromise the normal functions of vascular endothelial cells by activating oxidative stress-sensitive signaling pathways and subsequent proinflammatory events critical in the pathology of atherosclerosis and cardiovascular disease. To test this hypothesis, porcine endothelial cells were exposed to PCB 153 and to three coplanar PCBs (PCB 77, PCB 126, or PCB 169). In contrast to PCB 153, which is not a ligand for the Ah receptor (AhR), all coplanar PCBs disrupted endothelial barrier function. All coplanar PCBs increased expression of the CYP1A1 gene, oxidative stress (DCF fluorescence), and the DNA-binding activity of nuclear factor kappaB (NF-kappaB). PCB-induced oxidative stress was concentration-dependent, with PCB 126 exhibiting a maximal response at the lowest concentration (0.5 microM) tested. The increase in NF-kappaB-dependent transcriptional activity was confirmed in endothelial cells by a luciferase reporter gene assay. In contrast to PCB 153, coplanar PCBs that are AhR ligands increased endothelial production of interleukin-6. At 3.4 microM, expression of the adhesion molecule VCAM-1 was most sensitive to PCB 77 and 169. We also provide in vivo evidence, suggesting that binding to the AhR is critical for the proinflammatory properties of PCBs. Twenty hours after a single administration of PCB 77, VCAM-1 expression was increased only in wild-type mice, while mice lacking the AhR gene showed no increased staining for VCAM-1. These data provide evidence that coplanar PCBs, agonists for the AhR, and inducers of cytochrome P450 1A1, produce oxidative stress and an inflammatory response in vascular endothelial cells. An intact AhR may be necessary for the observed PCB-induced responses. These findings suggest that activation of the AhR can be an underlying mechanism of atherosclerosis mediated by certain environmental contaminants.
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PMID:Proinflammatory properties of coplanar PCBs: in vitro and in vivo evidence. 1207 26

Oxidative stress plays a pivotal role in the pathogenesis of atherosclerosis and can be effectively influenced by radical scavenging enzyme activity and expression. The vasoprotective effects of estrogens may be related to antioxidative properties. Therefore, effects of 17beta-estradiol on production of reactive oxygen species and radical scavenging enzymes were investigated. 17beta-estradiol diminished angiotensin II-induced free radical production in vascular smooth muscle cells (DCF fluorescence laser microscopy). 17beta-estradiol time- and concentration-dependently upregulated manganese (MnSOD) and extracellular superoxide dismutase (ecSOD) expression (Northern and Western blotting) and enzyme activity (photometric assay). Nuclear run-on assays demonstrated that 17beta-estradiol increases MnSOD and ecSOD transcription rate. Half-life of MnSOD mRNA was not influenced, whereas ecSOD mRNA was stabilized by estrogen. Copper-zinc SOD, glutathione-peroxidase, and catalase were not affected by estrogen. Estrogen deficiency in ovariectomized mice induced a downregulation of ecSOD and MnSOD expression, which was associated with increased production of vascular free radicals and prevented by estrogen replacement or treatment with PEG-SOD. In humans, increased estrogen levels led to enhanced ecSOD and MnSOD expression in circulating monocytes. Estrogen acts antioxidative at least to some extent via stimulation of MnSOD and ecSOD expression and activity, which may contribute to its vasoprotective effects.
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PMID:Modulation of antioxidant enzyme expression and function by estrogen. 1281 84

Polychlorinated biphenyls (PCBs), especially the more coplanar PCBs, have been shown to induce oxidative stress, various transcription factors, and subsequent inflammatory processes critical to atherosclerosis in vascular endothelial cells. Dietary flavonoids such as catechins and quercetin possess antioxidant and anti-inflammatory properties. To test the hypothesis that flavonoids can modify PCB-mediated endothelial cytotoxicity, endothelial cells were treated with epigallocatechin-3-gallate (EGCG; 5 to 50 muM) or quercetin (10 to 100 muM) with or without PCB 77 (3,3',4,4'-tetrachlorobiphenyl, 3.4 muM) for 6 h. EGCG and quercetin strongly, and in a concentration-dependent manner, inhibited oxidative stress induced by PCB 77 as measured by DCF fluorescence. The role of cytochrome P450 1A1 (CYP1A1) in the PCB-induced toxicity was investigated. EGCG at 50 muM and quercetin at 100 muM concentrations markedly inhibited CYP1A1 mRNA levels and enzyme activity. Furthermore, EGCG and quercetin downregulated the PCB 77-mediated increase in aryl hydrocarbon receptor (AhR)-DNA binding activity. These data suggest that protective effects of EGCG and quercetin are initiated upstream from CYP1A1 and that these flavonoids may be of value for inhibiting the toxic effects of PCBs on vascular endothelial cells.
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PMID:Dietary flavonoids modulate PCB-induced oxidative stress, CYP1A1 induction, and AhR-DNA binding activity in vascular endothelial cells. 1297 May 78

Angiotensin II type 1 (AT1) receptor activation as well as proinflammatory cytokines such as interleukin-6 (IL-6) are involved in the development and progression of atherosclerosis. The detailed underlying mechanisms including interactions between inflammatory agonists and the renin-angiotensin system are poorly understood. Stimulation of cultured rat aortic vascular smooth muscle cells (VSMCs) with IL-6 led to upregulation of AT1 receptor mRNA and protein expression, as assessed by Northern and Western blot experiments. Nuclear run-on and transcription blockade experiments showed that IL-6 increases AT1 receptor mRNA de novo synthesis but not mRNA stability. Preincubation of VSMCs with IL-6 resulted in an enhanced angiotensin II-induced production of reactive oxygen species, as assessed by DCF fluorescence laser microscopy. Treatment of C57BL/6J mice with IL-6 for 18 days increased vascular AT1 receptor expression (real-time RT-PCR) and angiotensin II-induced vasoconstriction, enhanced vascular superoxide production (L-012 chemiluminescence, DHE fluorescence), and impaired endothelium-dependent vasodilatation. These effects were completely omitted in AT1 receptor knockout mice (AT1A-/- mice). Upregulation of vascular AT1 receptor expression in vitro and in vivo is decisively involved in IL-6-induced propagation of oxidative stress and endothelial dysfunction. This interaction of the proinflammatory cytokine IL-6 with the renin-angiotensin system may represent an important pathogenetic mechanism in the atherosclerotic process.
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PMID:Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor. 1469 15

The present study was designed to investigate the hypothesis that trans fatty acids can induce apoptosis of human umbilical vein endothelial cells (HUVEC). To test this hypothesis apoptosis was measured in HUVEC treated with 0.1, 1.0 or 5.0 mM trans elaidic acid (t-18:1) or linoelaidic acid (t,t-18:2) for 24 hours. For the detection of apoptosis, TdT-mediated dUTP nick end labelling assay (TUNEL), cell binding of annexin V and propidium iodide uptake were measured. Active Caspase-3 and cleaved PARP (poly-ADP-ribose polymerase) were also measured in the cell lysate. Moreover, cellular ability to produce ROS (reactive oxygen species) was measured by DCF fluorescence Both acids studied induce both early (annexin-positive cells) and late stages of apoptosis (cells stained by propidium iodide) in a dose-dependent manner. Also the appearance of TUNEL-positive cells was induced by both trans fatty acids tested, in a dose dependent manner. Both trans acids induce apoptosis through their effect on Caspase-3 activity and on intracellular ROS production. It is worth emphasising that linoelaidic acid proved to be a more potent inducer of apoptosis and ROS production in endothelial cells than elaidic acid. The present studies suggest that trans fatty acids may play a role in damaging and death of vascular endothelial cells in atherosclerosis.
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PMID:Trans fatty acids induce apoptosis in human endothelial cells. 1639 18

Oxidized low-density lipoprotein (ox-LDL) plays an important in the development of atherosclerosis by stimulating the production of reactive oxygen species in endothelial cells, and thereby up-regulating vascular cell adhesion molecule-1 (VCAM-1). The objectives of the present study were to determine the effects of azelnidipine, a new calcium channel blocker, on the expression of VCAM-1 induced by 7-ketocholesterol, components of ox-LDL, and tumor necrosis factor-alpha (TNF-alpha). The scavenging activities of azelnidipine against superoxide, hydroxyl, and carbon-centered radicals were determined by electron spin resonance assay. The levels of intracellular reactive oxygen species were determined fluorometrically with the use of dichlorodihydrofluorescein diacetate (H(2)DCF-DA). Human aortic endothelial cells and U937 were used as endothelial cells and monocytic cells, respectively. The surface expression and mRNA levels of VCAM-1 were determined by enzyme immunoassay and RT-PCR performed on endothelial cell monolayers stimulated with 7-ketocholesterol or TNF-alpha. The numbers of monocytic cells adhering on the stimulated endothelial cells were counted in the microscopic fields. Translocation of p65 protein to the nucleus was estimated by fluorescence microscopy. Azelnidipine, but not nifedipine, reduced the signal intensity of 1,1-diphenyl-2-picrylhydrazyl radicals. Azelnidipine scavenged hydroxyl radicals, but not superoxide radicals. Intracellular levels of reactive oxygen species and RelA (p65) nuclear translocation in stimulated endothelial cells were reduced by azelnidipine. Azelnidipine significantly inhibited the expression of protein and mRNA of VCAM-1, and prevented the U937 cell adhesion to endothelial cells treated with 7-ketocholesterol or TNF-alpha. These results suggest that azelnidipine works as an anti-atherogenic agent by inhibiting the reactive oxygen species-dependent expression of VCAM-1 induced by 7-ketocholesterol and TNF-alpha.
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PMID:Azelnidipine, a new calcium channel blocker, inhibits endothelial inflammatory response by reducing intracellular levels of reactive oxygen species. 1691 61

Although estrogen replacement therapy may improve dampened endothelial function in postmenopausal women, the associated risk of breast and ovarian cancer has limited its long-term use. Identifying effective alternative remedy with less carcinogenicity is in serious demand. This study was designed to examine the effect of the phytoestrogen alpha-zearalanol (alpha-ZAL) on homocysteine-induced endothelin-1 (ET-1) induction, reactive oxygen species (ROS) production and transcription pathways in human umbilical vein endothelial cells (HUVECs). ROS was measured by DCF fluorescent microscopy. Homocysteine-induced expression of ET-1 mRNA, ERK, pERK and c-jun/AP-1 protein was measured using RT-PCR and Western blot analysis, respectively. ET-1 secretion was determined by the enzymatic immunoassay. Transcriptional factor AP-1 expression in response to alpha-ZAL, homocysteine or both was evaluated by transient transfection assay. Our data revealed that alpha-ZAL ablated homocysteine-elicited ET-1 secretion, upregulated ET-1 mRNA and homocysteine-induced ROS accumulation without any effects by itself. alpha-ZAL also nullified homocysteine-induced increase in c-Jun/AP-1 expression/activity without eliciting any effect by itself. Collectively, our data indicated that alpha-ZAL may antagonize homocysteine-induced ET-1 gene induction, ROS accumulation, activation of ERK signaling pathway and AP-1 transcriptional factor, all of which may contribute to alpha-ZAL-induced beneficial effect on endothelial function.
Atherosclerosis 2008 Apr
PMID:Phytoestrogen alpha-zearalanol inhibits homocysteine-induced endothelin-1 expression and oxidative stress in human umbilical vein endothelial cells. 1790 May 92

Oxidatively modified LDL is generally accepted to be an important elicitor of pro-mitotic, pro-inflammatory, and atherogenic effects in vascular cells. The uptake of oxLDL and concomitant activation of the O(2)*-producing NAD(P)H oxidase and/or oxLDL as a self-contained emitter of O(2)* are believed to trigger these malfunctions. The following observations allowed reinvestigating the mode of oxLDL-induced stress: (1) we observed that artery smooth muscle primary cells internalize fluorescently labelled oxidized or acetylated LDL considerably less efficient than endothelial cells. (2) Both types of cells, however, displayed an oxLDL concentration dependent level of oxidative stress as monitored by the oxidation of carboxy-H2DCFDA to fluorescent carboxy-DCF. A dose dependent decrease of dihydroethidine oxidation to oxyethidine implied an oxLDL-induced depletion of the cellular energy pool. The release of O(2)* by exogenous oxLDL, as postulated above, did not sufficiently explain intracellular stress because the fluorescence was only marginally blocked by antioxidative enzymes (SOD, catalase) or substances (L-NAME, DMSO, DMHP, DMTU). We were able to reveal a third mode of oxLDL-induced stress by showing with the help of a fluorescent, oxidizable lipid analogue (BODIPY 581/591 C(11)) that oxLDL-derived lipid peroxides and radicals migrate into cellular membranes giving rise to a chronic inoculation of the vascular cells with oxidative chain reactions. The novel data may help to design adequate therapeutic strategies against oxLDL-induced cardiovascular diseases.
Atherosclerosis 2008 Apr
PMID:Transmission of oxLDL-derived lipid peroxide radicals into membranes of vascular cells is the main inducer of oxLDL-mediated oxidative stress. 1795 Feb 98

Migration and proliferation of vascular smooth muscle cells (VSMCs) are important events in the progression of atherosclerosis. Insulin-like growth factor I (IGF-1) possesses both antiapoptotic and mitogenic/motogenic effects in VSMCs although the influence of life cycle on IGF-1-induced effects is unclear. This study was designed to evaluate the effect of IGF-1 on migration, proliferation, and signaling mechanisms in VSMCs from early (3-5) to late (20-22) passages. Migration, proliferation, and cell survival were measured using monolayer wounding, 3[H]-thymidine incorporation and MTT assay, respectively. Akt and ERK, which are critical to proliferation, differentiation and migration, were examined using Western blot analysis. DCF-DA fluorescence was used to quantify Reactive Oxygen Species (ROS) production. Late-passage VSMCs exhibited significantly higher basal cell proliferation and enhanced sensitivity to IGF-1-stimulated migration compared to cells from early-passages. Phosphorylated Akt and ERK levels were significantly higher in late-passage cells compared to early-passage, which was further enhanced by IGF-1 treatment. Late-passage cells exhibited higher levels of ROS production compared to early-passage, cells. IGF-1 did not significantly alter ROS levels in either passage. Expression of the cell cycle regulator p53, p21, and p16 was not affected by repeated passaging of cells. These results indicated that repeated passaging of VSMCs exhibits a phenotype which has higher proliferative capacity. Activation of trophic signaling molecules such as ERK1/2 and Akt and generation of ROS may represent the mechanisms by which repeated passages of VSMCs acquire a motogenic and mitogenic phenotype.
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PMID:Impact of insulin-like growth factor-I on migration, proliferation and Akt-ERK signaling in early and late-passages of vascular smooth muscle cells. 1796 Apr 99

Vascular inflammatory process has been suggested to play a key role in the initiation and progression of atherosclerosis, a major complication of diabetes mellitus. Lycopus lucidus Turcz. has been used as an oriental traditional medicine including Korea and its crude drug is known to have an anti-inflammatory effect. Thus we investigated whether the aqueous extract of the leaves of L. lucidus Turcz. (ALT) suppresses vascular inflammatory process induced by high glucose in primary cultured human umbilical vein endothelial cells (HUVEC). Western blot analysis revealed that incubation of HUVEC with high glucose increased cell adhesion molecules (CAMs) expression levels. However, high glucose-induced increase of CAMs expression was significantly attenuated by pretreatment with ALT in a dose-dependent manner. The enhanced cell adhesion between monocyte and HUVEC induced by high glucose was also blocked by pretreatment with ALT. High glucose-induced hydrogen peroxide production and DCF-sensitive intracellular reactive oxygen species (ROS) formation. Pretreatment with ALT inhibited high glucose-induced ROS formation. In addition, ALT suppressed the translocation and promoter transcriptional activity of NF-kappaB increased in high glucose condition. Taken together, the present data suggested that ALT could suppress high glucose-induced vascular inflammatory process, which may be closely related with the inhibition of ROS and NF-kappaB activation in HUVEC.
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PMID:Lycopus lucidus inhibits high glucose-induced vascular inflammation in human umbilical vein endothelial cells. 1808 68


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