UMLS:C0004153 - FACTA Search

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Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because of structural similarities between low density lipoproteins (LDL) and lipoprotein (a) (Lp(a)), we have investigated the properties and the functional activities of oxidized Lp(a) and focused on whether oxidized Lp(a), like oxidized LDL, can induce monocyte differentiation and adhesion of monocytic cells to endothelial cells grown in culture. Oxidized Lp(a), prepared in vitro by cupric ion oxidation, gave absorption curves of conjugated dienes with a lag-phase of 61.7 +/- 6.6 min (mean +/- S.D.) as compared to 85.2 +/- 7.2 min (n = 6, P < 0.01) for oxidized LDL from the same donors and at equimolar concentrations. Degradation of oxidized 125I Lp(a) by the monocytic cell line U937 at 37 degrees C was 1.6 +/- 0.3 nmol/g of cell protein, significantly (P < 0.01) greater than the degradation of oxidized 125I-LDL, which was 1.15 +/- 0.2 nmol/g of cell protein. Equimolar concentrations of oxidized Lp(a) and LDL inhibited the growth of U937 by 82 +/- 8.2% and 64 +/- 7.1%, respectively, when compared with the effect (negligible) produced by native Lp(a) and LDL. In addition, equimolar concentrations of oxidized Lp(a) and LDL induced adhesion molecule, Mac-1 (CD 11b), expression in U937 by 64 +/- 7.1% and 58 +/- 6.1% (P > 0.05), respectively, of the effect produced by phorbol esters (PMA) (P < 0.01). U937 cells incubated with oxidized Lp(a) and LDL, showed an adherence to cultured endothelial cells at 42 +/- 5.2% and 34 +/- 4.8%, respectively (P < 0.05), of the adherence shown by the same cells activated by PMA (P < 0.01). Our results suggest that oxidized Lp(a) like oxidized LDL plays an important role in the development of atherogenesis by inducing adhesion of monocytes to the arterial intimal and by stimulating intimal monocytes to differentiate into macrophages.
Atherosclerosis 1996 Jun
PMID:Oxidized lipoprotein (a) induces cell adhesion molecule Mac-1 (CD 11b) and enhances adhesion of the monocytic cell line U937 to cultured endothelial cells. 878 41

It is generally accepted that the foam cells in atherosclerotic lesions are derived mainly from monocytes/macrophages. We investigated whether the macrophage-derived foam cells, isolated from the atherosclerotic lesions of cholesterol-fed rabbits, would exhibit properties similar to those of blood monocytes in vitro and whether the cholesterol concentration of the macrophage-derived foam cells would decrease in the presence of an appropriate cholesterol acceptor in culture. We found that most (> 98%) of the foam cells isolated from atherosclerotic lesions were positive for anti-monocyte-macrophage antibody and nonspecific esterase. While almost all (> 98%) of the foam cells exhibited NaF-resistant, nonspecific esterase activity, the blood monocytes exhibited no such activity. Macrophage-derived foam cells contained larger amounts of cholesterol, most of it esterified, than the blood monocytes. Although blood monocytes exhibited a substantial amount of lysozyme, the freshly isolated, macrophage-derived foam cells showed no detectable lysozyme activity. The production of superoxide by macrophage-derived foam cells stimulated by PMA or opsonized zymosan was lower than that of stimulated monocytes. The cholesterol concentration of macrophage-derived foam cells decreased during five days of culture in the presence of an appropriate acceptor, such as normal and hypercholesterolemic rabbit serum and high density lipoprotein, although the rate of decrease was slow. Results suggest that macrophage-derived foam cells may be involved in both the progression and the regression of early atherosclerotic lesions.
Atherosclerosis 1997 Dec
PMID:Characteristics of macrophage-derived foam cells isolated from atherosclerotic lesions of rabbits. 943 Mar 74

Although the body status of zinc and copper in cardiovascular disease (CVD) has been shown to be important little is known about the effect of these trace element alterations on lipolytic enzyme activities in atherosclerosis human subjects. The aim of the present study was to evaluate the multiple relationships between lipase (GEH = glycerol ester hydrolase, EC 3.1.1.3) activity, zinc, copper and lipid concentrations in serum and the arterial wall of men with atherosclerosis obliterans (AO) and abdominal aortic aneurysm (AA). The mean concentrations of zinc and copper in serum were found to be higher in AO in comparison to AA. Low but significant correlation coefficients for zinc and lipase catalytic activity (r > or = 0.64) and lipase metabolic activity GEH/TAG (r > or = 0.67) were calculated in serum in AA. Multiple correlation coefficients (R) for three variables GEH-Zn-Cu were found to be significant for both AO and AA (R > or = 0.45 and 0.68, respectively) in serum but not in the arterial wall. Multiple relations for GEH/TAG-HDL-C (LDLC)-Zn(Cu) were found to be significant (R > or = 0.63) in serum in AA. The results indicate the influence of zinc and copper on the activity of lipase and lipid concentrations and suggest that the multiple relations may provide a better understanding of the role these elements play in atherosclerosis than relations between 2 substances.
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PMID:Serum glycerol ester hydrolase activity is related to zinc and copper concentrations in atherosclerosis obliterans and aneurysm. 963 11

Vascular oxidative stress brought about by superoxide radicals and oxidized low-density lipoproteins (oxLDL) is a major factor contributing to decreased NO-dependent vasodilator function in hypercholesterolemia and atherosclerosis. We investigated whether chronic administration of L-arginine (2% in drinking water) or of alpha-tocopherol (300 mg/day) improves endothelium-dependent vasodilator function and systemic NO production, reduces vascular oxidative stress, and reduces the progression of atherosclerosis in cholesterol-fed rabbits with pre-existing hypercholesterolemia. Systemic NO production was assessed as urinary nitrate excretion; oxidative stress was measured by urinary 8-iso-PGF2alpha excretion in vivo, by lucigenin-enhanced chemiluminescence of isolated aortic rings ex vivo, and by copper-mediated LDL oxidation in vitro. Endothelium-dependent relaxation was almost completely abrogated in cholesterol-fed rabbits. Urinary nitrate excretion was reduced by 46+/-10%, and 8-iso-PGF2alpha excretion was increased by 61+/-18% as compared to controls (each P <0.05). Vascular superoxide radical release stimulated by PMA ex vivo was increased by 273+/-93% in this group, and the lag time of LDL oxidation was reduced by 35+/-6% (each P <0.05). Treatment with L-arginine and alpha-tocopherol reduced intimal lesion formation (by 68+/-6 and 4+/-11%, respectively; P <0.05) and improved endothelium-dependent relaxation. Both treatments also normalized urinary 8-iso-PGF2alpha excretion. L-Arginine increased urinary nitrate excretion by 43+/-13% (P <0.05) and reduced superoxide radical release by isolated aortic rings to control levels, which was unaffected by vitamin E treatment. By contrast, vitamin E dramatically increased the resistance of isolated LDL to copper-mediated oxidation in vitro by 178+/-7% (P <0.05), which was only marginally prolonged by L-arginine. Intimal thickening was reduced by both treatments. We conclude that both L-arginine and alpha-tocopherol reduce the progression of atherosclerotic plaques in cholesterol-fed rabbits. However, while L-arginine increases NO formation and reduces superoxide release, alpha-tocopherol antagonizes mainly oxLDL-related events in atherogenesis. Thus, both treatments reduce urinary isoprostane excretion and improve endothelium-dependent vasodilation via different mechanisms.
Atherosclerosis 1998 Nov
PMID:Dietary L-arginine and alpha-tocopherol reduce vascular oxidative stress and preserve endothelial function in hypercholesterolemic rabbits via different mechanisms. 986 36

Aggregated low density lipoprotein (LDL) is taken up by macrophages at enhanced rate, leading to macrophage cholesterol accumulation and foam cell formation. Since macrophages were shown to mediate self aggregation of modified forms of LDL, we sought to study the effect of macrophages on the susceptibility of native LDL to aggregation. Incubation of LDL (100 microg of protein/ml) with J-774A.1 macrophage-like cell line for 18 h at 37 degrees C, led to a 114 and 56% enhanced susceptibility of LDL to aggregation by vortexing and by Bacillus cereus SMase respectively. Macrophage conditioned media (MCMs) that were obtained from J-774A.1 cells also enhanced the susceptibility of LDL to aggregation by vortexing and SMase by 134 and 75% respectively, suggesting the involvement of macrophage secretory products in the enhanced aggregation of LDL. As proteoglycans were shown to be involved in lipoprotein aggregation, we analyzed the possible involvement of macrophage-released proteoglycans in LDL aggregation. Incubation of LDL (100 microg protein/ml) with 25 microg of proteoglycans that were isolated from MCM led to a dose-dependent enhanced susceptibility of LDL to aggregation by vortexing or by SMase by up to 62 and 77% respectively. The stimulatory effect of the MCMs on LDL aggregation was markedly reduced upon MCMs treatment with the glycosaminoglycan hydrolyzing enzyme chondroitinase ABC, chondroitinase AC, but not heparinase. On the contrary, incubation of LDL (100 microg of protein/ml) with increasing concentrations (up to 50 microg/ml) of chondroitin sulfate, or heparan sulfate enhanced the susceptibility of LDL to aggregation by up to 98 or by only 18% respectively, in comparison with non-treated LDL. Since macrophages under atherogenic conditions (cholesterol-loading, cellular lipid peroxidation and activation) demonstrate enhanced secretion of proteoglycans, we finally studied the effect of J-774A.1 macrophages on the susceptibility of native LDL to aggregation under the above atherogenic conditions. Incubation of LDL with cholesterol-loaded macrophages led to a 62% enhanced susceptibility of LDL to undergo aggregation by vortexing, in comparison with LDL that was incubated with non-loaded cells. Macrophage activation with phorbol myristate acetate (5 microM of PMA) also significantly increased cell-mediated aggregation of LDL by 50%, in comparison with non-activated cells. Lipid peroxidized macrophages obtained by cell treatment with either FeSO4 (50 microM), or angiotensin II (10(-7) M) enhanced the susceptibility of LDL to aggregation by 22 or by 39% respectively. These results suggest that under atherogenic conditions, macrophages release proteoglycans, and mainly chondroitin sulfate, which can contribute to cell-mediated formation of aggregated LDL, a potent inducer of macrophage foam cells which are the hallmark of early atherogenesis.
Atherosclerosis 1999 Jan
PMID:Macrophage released proteoglycans are involved in cell-mediated aggregation of LDL. 992 May 6

Hydroxymethylglutaryl-Coenzyme A (HMG-CoA) reductase inhibitors were shown to be effective in primary and secondary prevention of coronary heart disease. The beneficial effect of statins is generally attributed to their cholesterol lowering activity. However recent work points to additional cholesterol independent effects of these drugs on cellular signal transduction. In this study it was investigated whether HMG-CoA reductase inhibition could affect induction of the transcription factors c-Jun and c-Fos in smooth muscle cells, which play an important role in atherogenesis. SMC were preincubated for 12 h with or without lovastatin (5 microM) and subsequently stimulated with platelet derived growth factor (PDGF, 10 ng/ml) or angiotensin II (0.1 microM) for 1, 2, 4 and 12 h or with phorbol myristate acetate (100 pM) for 2 h. Stimulation in the absence of the HMG-CoA reductase inhibitor led to a significant induction of c-Jun and c-Fos. Lovastatin inhibited, PDGF-, angiotensin II- and PMA-mediated induction. Concomitant addition of mevalonate, farnesylpyrophosphate and geranylgeranylpyrophosphate prevented the effects of HMG-CoA reductase inhibition resulting in rescued expression of c-Jun and c-Fos. The suppression of these transcription factors was associated with a complete growth arrest. Viability was not affected by pretreatment with the HMG-CoA reductase inhibitor. The data demonstrate that lovastatin can suppress PDGF- and angiotensin II-mediated induction of c-Jun and c-Fos protein in human SMC. This inhibitory effect may prevent activation of numerous growth factor- and cell cycle- genes. Whether these findings contribute to the effects of statins in atherosclerosis remains to be further investigated.
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PMID:Effects of HMG-CoA reductase inhibition on PDGF- and angiotensin II- mediated signal transduction: suppression of c-Jun and c-Fos in human smooth muscle cells in vitro. 1020 88

T cells take part in the chronic inflammatory reaction in atherosclerotic plaques, but their specific role in atherosclerosis has not yet been fully elucidated. Nevertheless, one may anticipate that activated T cells may secrete cytokines capable of modulating the morphology and hence the stability of plaques by regulating cell proliferation, lipid metabolism, and extracellular matrix (ECM) synthesis and/or degradation. This study has been designed to investigate the functional properties of T cells in atherosclerotic lesions. For this purpose, T-cell clones were generated from atherosclerotic plaques isolated from human aortas obtained at autopsy from six subjects. Cloned cells were activated with PMA and OKT-3 to initiate cytokine production and cytokine profiles of CD4-positive clones were measured by ELISA. The majority of the T-cell clones (125/155, 81 per cent) produced both interferon (IFN)-gamma and interleukin (IL)-4 (type 0 cytokine profile). Moreover, the production of IFN-gamma was dominant in the majority of these clones. A type 1 cytokine profile (high levels of IFN-gamma and low levels of IL-4) was found in 17 per cent of the clones (27/155). Only three clones (2 per cent) showed a type 2 cytokine secretion pattern (high levels of IL-4 and low levels of IFN-gamma). No cytolytic activity could be established in plaque-derived T cells. Our results show that the T-cell population in atherosclerotic lesions is heterogeneous, but the most dominant T cell by far is the one with a type 0 cytokine profile. The dominant secretion of IFN-gamma by T-cell clones suggest an important role for plaque T cells in modulating the growth and differentiation of other cells, such as macrophages and smooth muscle cells in atherosclerotic plaques.
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PMID:Cytokine secretion profiles of cloned T cells from human aortic atherosclerotic plaques. 1039 61

Exaggerated postprandial lipemia is believed to be atherogenic and to influence risk of thrombosis. The postprandial effects on plasma triacylglycerol concentration, factor VII coagulant activity (FVII(c)) and activated FVII concentration (FVII(a)) of five high fat meals (5.2 MJ, 90 g fat) enriched with medium triacylglycerols (MCT, 8:0+10:0), palmitate(16:0), stearate (18:0), elaidate(18:1 trans) and oleate(18:1 cis) were compared with those following a low fat meal (5.2 MJ,10 g fat) in 16 healthy subjects using a randomized crossover design. Postprandial lipemia measured as the area under the curve (AUC arbitrary units) for plasma triacylglycerol concentration (mean+/-SE) was greater following the oleate (5.8+/-1. 05), elaidate (4.3+/-0.79) and palmitate (4.1+/-0.64) meals compared with stearate (2.0+/-0.45) and MCT (1.1+/-0.47) meals. Fatty acid analyses of the chylomicron lipids suggested that approximately one fifth of the dietary stearate was not absorbed. FVII(c) increased following the oleate, elaidate and palmitate meals and fell following the low fat meal; the increase in FVII(c) was correlated with the AUC for plasma TAG (r=0.34; P=0.001). FVII(a) concentration increased following all high fat meals but not following the low fat meal. The increase in FVII(a) at 7 h was greater after the oleate meal than after the stearate and MCT meals. These results do not support the hypothesis that dietary stearate and elaidate are responsible for the postprandial increases in FVII associated with high fat intakes.
Atherosclerosis 2000 Apr
PMID:Influence of fatty acid chain length and cis/trans isomerization on postprandial lipemia and factor VII in healthy subjects (postprandial lipids and factor VII). 1072 92

Oxidized low-density lipoprotein (OX-LDL) contributes significantly to the development of atherosclerosis. However, the mechanisms of OX-LDL-induced vascular smooth muscle cell (VSMC) proliferation are not completely understood. Therefore, we investigated the effect of OX-LDL on cell proliferation associated with a specific pattern of mitogen-activated protein kinase (MAPK) by [3H]thymidine incorporation and p42/p44 MAPK phosphorylation in canine cultured VSMCs. OX-LDL-induced [3H]thymidine incorporation and p42/p44 MAPK phosphorylation in a time- and concentration-dependent manner in VSMCs. Pretreatment of these cells with pertussis toxin (PTX) for 24 hours attenuated the OX-LDL-induced [3H]thymidine incorporation and p42/p44 MAPK phosphorylation, indicating that these responses were mediated through a receptor coupled to a PTX-sensitive G protein. In cells pretreated with PMA for 24 h and with either the PKC inhibitor staurosporine or the tyrosine kinase inhibitor genistein for 1h, substantially reduced the [3H]thymidine incorporation and p42/p44 MAPK phosphorylation in response to OX-LDL. Removal of Ca(2+) by addition of BAPTA/AM plus EGTA significantly inhibited OX-LDL-induced [3H]thymidine incorporation and p42/p44 MAPK phosphorylation, indicating the requirement of Ca(2+) for these responses. OX-LDL-induced [3H]thymidine incorporation and p42/p44 MAPK phosphorylation was completely inhibited by PD98059 (an inhibitor of MEK1/2) and SB203580 (an inhibitor of p38 MAPK). Furthermore, we also showed that overexpression of dominant negative mutants of Ras (RasN17) and Raf (Raf-301) completely suppressed MEK1/2 and p42/p44 MAPK activation induced by OX-LDL and PDGF-BB, indicating that Ras and Raf may be required for activation of these kinases. Taken together, these results suggest that the mitogenic effect of OX-LDL is mediated through a PTX-sensitive G-protein-coupled receptor that involves the activation o Ras/Raf/MEK/MAPK pathway similar to those of PDGF-BB in canine cultured VSMCs.
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PMID:Activation of mitogen-activated protein kinase by oxidized low-density lipoprotein in canine cultured vascular smooth muscle cells. 1078 27

Increased oxidative stress has been reported in vivo in the diabetic state via the production of reactive oxygen species (ROS). Such stress is bound to play a key role on activation of circulating monocytes, leading to the accelerated atherosclerosis observed in diabetics. However the exact molecular mechanisms of monocyte activation by high glucose is currently unclear. Here, we demonstrate that chronic high glucose (CHG) causes a dramatic increase in the release of the inflammatory cytokine tumor necrosis factor alpha (TNFalpha), at least in part through enhanced TNFalpha mRNA transcription, mediated by ROS via activation of transcription factors nuclear factor kappaB (NF-kappaB) and activating protein-1 (AP-1). TNFalpha accumulation in the conditioned media was increased 10-fold and mRNA levels were increased 11.5-fold by CHG. The following observations supported that both NF-kappaB and AP-1 mediated enhanced TNFalpha transcription by CHG: 1) A 295-base pair fragment of the proximal TNFalpha promoter containing NF-kappaB and AP-1 sites reproduced the effects of CHG on TNFalpha transcription in a luciferase reporter assay, 2) mutational analyses of both NF-kappaB and the AP-1 sites abrogated 90% of the luciferase activity, 3) gel-shift analysis using the binding sites showed activation of NF-kappaB and AP-1 in CHG nuclear extracts, and 4) Western blot analyses demonstrated elevated nuclear levels of p65 and p50 and decreased cytosolic levels of IkappaBalpha in CHG-treated monocytes. That ROS acted as a key intermediate in the CHG pathway was supported by the following evidence: 1) increased superoxide levels similar to those observed with PMA or TNFalpha, 2) increased phosphorylation of stress-responsive mitogen-activated protein kinases p38 and JNK-1, 3) counteraction of the effects of CHG on TNFalpha production, the 295TNFluc reporter activity, activation of NF-kappaB, and repression of IkappaBalpha by antioxidants and p38 mitogen-activated protein kinase inhibitors. The study suggests that ROS function as key components in the regulatory pathway progressing from elevated glucose to monocyte activation.
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PMID:Molecular mechanisms of tumor necrosis factor alpha gene expression in monocytic cells via hyperglycemia-induced oxidant stress-dependent and -independent pathways. 1083 98

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