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

Low density lipoprotein (LDL), if it becomes oxidized, develops several unique properties including the capacity to provoke endothelial cytotoxicity via metal-catalyzed free radical-mediated mechanisms. As were previously have shown that iron-catalyzed oxidant injury to endothelial cells can be attenuated by the addition of exogenous iron chelators such as the lazaroids and deferoxamine, we have examined whether the endogenous iron chelator, ferritin, might provide protection from oxidized LDL. LDL oxidized by iron-containing hemin and H2O2 is toxic to endothelial cells in a time- and dose-dependent fashion. Endothelial cell ferritin content is increased by pretreatment of cells with iron compounds or by the direct addition of exogenous apoferritin; ferritin-loaded cells are markedly resistant to the toxicity caused by oxidized LDL. Iron inactivation by ferritin depends on its ferroxidase activity. When a recombinant human ferritin heavy chain mutant, 222, which is devoid of ferroxidase activity, is added to endothelial cells, unlike the excellent protection afforded by the wild-type recombinant heavy chain, endothelial cells are not protected from oxidized LDL. To assess the in vivo relevance of our observation, we examined human coronary arteries of cardiac explants taken from patients with end-stage atherosclerosis. Large amounts of immunoreactive ferritin are focally detected in atherosclerotic lesions, specifically in the myofibroblasts, macrophages, and endothelium without a notable increase in Prussian blue-detectable iron. These findings suggest that ferritin may modulate vascular cell injury in vivo.
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PMID:Ferritin protects endothelial cells from oxidized low density lipoprotein in vitro. 767 89

Exocytosis from Weibel-Palade bodies, the secretory granules of vascular endothelial cells, causes the rapid release of von Willebrand factor (vWF), an adhesive glycoprotein involved in primary hemostasis, and cell surface expression of P-selectin, a membrane protein involved in neutrophil binding. Thus, exocytosis may represent a link between hemostasis and inflammation. We investigated the effect of reactive oxygen intermediates (ROIs) on vWF secretion. Incubation of cultured endothelial cells with xanthine oxidase (XO), which generates superoxide anions (O2-), induces a potent, rapid secretory response. However, vWF release was not observed in response to H2O2. Extracellular, subendothelial vWF deposits typically seen after exocytosis from Weibel-Palade bodies were observed after exposure to XO. XO caused a rapid, sustained increase in intracellular free calcium concentration ([Ca2+]i). vWF secretion was markedly inhibited by BAPTA-AM, a cell-permeant calcium chelator. Removal of extracellular calcium did not inhibit vWF release, although the sustained phase of the [Ca2+]i increase was suppressed. These results suggest that XO-induced vWF release is mediated by the initial increase in [Ca2+]i which is caused by calcium mobilization from intracellular stores rather than by calcium influx. Exocytosis from Weibel-Palade bodies may contribute to the pathogenic effect of ROIs in atherosclerosis and inflammation.
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PMID:Reactive oxygen intermediates induce regulated secretion of von Willebrand factor from cultured human vascular endothelial cells. 775 49

Oxidation of human plasma lipoprotein (LP) was studied in the presence of exogenous hypochlorite anion (OCl-) or OCl- generated in the "myeloperoxidase + H2O2 + Cl-" system. OCl- effectively initiates peroxidation of lipids extracted from LP and those within LP particles, as can be judged from accumulation of secondary (thiobarbituric acid [TBA] reactive) and final (Schiff bases) products of lipid peroxidation (LPO) in LP after incubation with myeloperoxidase or exogenous OCl-. Very low density and low density lipoproteins classified as atherogenic LP are more sensitive to OCl(-)-induced LPO than high density lipoproteins. These data allow us to propose that OCl- secreted by activated neutrophils and monocyte-macrophages can produce oxidative modification of LP in vivo. The latter is known as a risk factor in the development of atherosclerosis.
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PMID:Peroxidation of human blood lipoproteins induced by exogenous hypochlorite or hypochlorite generated in the system of "myeloperoxidase + H2O2 + Cl-". 800 9

Low-density lipoproteins (LDL) oxidized by oxygen radicals are a potent atherogenic stimulus. Chemically modified LDL are internalized by macrophages via a specific cell surface receptor that was termed the scavenger receptor, and could induce foam cell transformation. Post-translational nonenzymatic glycosylation of low density lipoprotein (LDL) occurs in vivo in diabetic patients. Glycosylated LDL (glcLDL) is degraded by macrophages in part by the classic LDL-receptor and in part by the scavenger receptor. This latter mechanism may contribute to the formation of foam cells and acceleration of atherosclerosis in diabetes mellitus. Oxygen free radicals (ORs) could induce LDL peroxidation and subsequent formation of foam cells. Glycosylation may alter protein conformation. A free radical is any chemical species that has an unpaired electron. This property renders it highly chemically reactive. When a radical reacts with a non radical another free radical is generated. This characteristic enables radicals to trigger chain reactions. Oxygen radicals are: superoxide anion (.O2-), hydroxyl radical (.OH) and hydrogen peroxide (H2O2). Thus, the aim of this study was to investigate whether glcLDL are susceptible to peroxidative modification by ORs. GlcLDL was prepared incubating LDL with 40 mM glucose in sterile phosphate-buffer-EDTA 1 mM for 10 days at 37 degrees C. Control LDL (cLDL) was similarly incubated with buffer but without glucose. After this preparation both forms of LDL were oxidized by CuSO4 (15 microM for 20 hours at 37 degrees C) or by xanthine/xanthine oxidase (X:2 mM/XO: 100 mU for 20 hours at 37 degrees C).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The peroxidation of human glycosylated low-density lipoproteins is mediated by the superoxide radical: the protective effects of superoxide dismutase]. 808 16

Oxidative modification of low density lipoprotein (LDL) has been suggested as a causal step in atherosclerosis, and both redox-active transition metal ions and superoxide (O2.-) have been implicated in this process. In order to determine the mechanisms of metal ion-dependent oxidation of LDL in the presence of O2.-, LDL was exposed to hypoxanthine (HX) and purified xanthine oxidase (XO) without and with added CuCl2 or Fe(3+)-citrate. Production of O2.- and hydrogen peroxide (H2O2) at pH 7.4 by the HX/XO system in the absence of metal ions was not sufficient to oxidize LDL. Preincubation of LDL with Cu2+ or Fe(3+)-citrate with subsequent removal of metal ions not tightly bound to the lipoprotein did not enable the HX/XO system to oxidize LDL. However, incubation of LDL with HX/XO and Cu2+ resulted in extensive modification of LDL. Exposure of LDL to Cu2+ alone also led to extensive modification, although the LDL was initially free of detectable amounts of lipid hydroperoxides (LOOH), i.e., < 0.005 molecules of LOOH per LDL particle. Although HX/XO and Cu2+ did not produce detectable amounts of O2.- or aqueous hydroxyl radicals (HO.), oxidation of LDL under these conditions was partially inhibited by superoxide dismutase, and completely inhibited by the HO. scavenger thiourea. In contrast to Cu(2+)-mediated oxidation of LDL, oxidation mediated by Fe(3+)-citrate was strictly dependent upon O2.-, as it was abolished by omission of the HX/XO system or by addition of superoxide dismutase to this system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of copper- and iron-dependent oxidative modification of human low density lipoprotein. 824 25

Oxidant injury of the vascular endothelium is considered an early event in the pathogenesis of atherosclerosis. The model of oxidant injury is crucial to the investigation of antioxidants. In the present study, a convenient in vitro model of oxidant injury induced by hydrogen peroxide (H2O2) was developed using bovine pulmonary artery endothelial cells (PAEC). Viability of PAEC grown in 96-well culture plates was determined with methylthiazol tetrazolium (MTT) colorimetric assay. Cell membrane integrity was measured by lactate dehydrogenase (LDH) release from PAEC grown in 24-well plates. Malondialdehyde (MDA, a product of lipid peroxidation) in PAEC grown in 6-well plates was detected by a thiobarbituric acid fluorometric assay. Incubation of H2O2 with PAEC caused a dose-dependent decrease of cell viability, an increase of LDH release, and an elevation of MDA production. MTT assay was convenient, quantitative, non-radioactive, and suitable for testing a large number of samples. The fluorometric assay for measuring MDA production in endothelial cells used 6-well plates instead of 80-cm2 flasks employed by previous investigators. The use of multiwell culture plates in these assays made it possible for more samples to be tested in any single experiment. The three assays are reproducible with low intraplate and interplate coefficients of variation. This in vitro model is suitable for screening antioxidants and for studying pharmacodynamics at the cellular level.
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PMID:A simplified in vitro model of oxidant injury using vascular endothelial cells. 835 64

Several findings pint out the occurrence of a strict relationship between lipoproteins and immunoresponsiveness. In this regard, in vitro lipoproteins pretreatment of mononuclear cell suspensions leads to an inhibition of Natural Killer (NK) cytotoxicity or T- and B-mediated immune functions. These results have an in vivo counterpart, since an impairment of either T-driven B cell polyclonal differentiation or phagocyte chemotaxis, phagocytosis and killing has been shown in patients with type IIa and type IIb primary hyperlipoproteinaemia. On the contrary, these activities fall within normal range in type IV hyperlipoproteinaemic subjects. To further address the potential role of polymorphonuclear cells (PMN) in atherosclerotic process, in the present report PMN-mediated superoxide anion (O2-) generation, hydrogen peroxide (H2O2) production, beta-glucuronidase and myeloperoxidase release have been assessed in similar groups of patients. Results provide a clearcut evidence for a significant enhancement of oxidative metabolism by either suspended or adherent to plastic PMN in type IIa primary hyperlipoproteinaemia only. These data were further confirmed by the observation that the same cell suspensions exhibit a significant increase of H2O2 generation and/or beta-glucuronidase and myeloperoxidase release. By contrast, PMN metabolic pathway in type IIb and type IV patients mimics that observed in healthy individuals. In the light of the well known increase of serum low-density lipoproteins (LDL) in type IIa primary hyperlipoproteinaemia, these findings suggest that also PMN may play an important role in the development of atherosclerosis. The augmented oxidative responsiveness may, in fact, give rise to LDL oxidation, which is in turn responsible for foam cell generation through an exaggerated uptake of oxidized LDL by macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxidative burst and lysosomal enzyme release by polymorphonuclear cells in type IIa, type IIb and type IV primary hyperlipoproteinaemia. 835 3

Elevated levels of homocysteine are associated with an increased risk of atherosclerosis and thrombosis. The reactivity of the sulfhydryl group of homocysteine has been implicated in molecular mechanisms underlying this increased risk. There is also increasingly compelling evidence that thiols react in the presence of nitric oxide (NO) and endothelium-derived relaxing factor (EDRF) to form S-nitrosothiols, compounds with potent vasodilatory and antiplatelet effects. We, therefore, hypothesized that S-nitrosation of homocysteine would confer these beneficial bioactivities to the thiol, and at the same time attenuate its pathogenicity. We found that prolonged (> 3 h) exposure of endothelial cells to homocysteine results in impaired EDRF responses. By contrast, brief (15 min) exposure of endothelial cells, stimulated to secrete EDRF, to homocysteine results in the formation of S-NO-homocysteine, a potent antiplatelet agent and vasodilator. In contrast to homocysteine, S-NO-homocysteine does not support H2O2 generation and does not undergo conversion to homocysteine thiolactone, reaction products believed to contribute to endothelial toxicity. These results suggest that the normal endothelium modulates the potential, adverse effects of homocysteine by releasing EDRF and forming the adduct S-NO-homocysteine. The adverse vascular properties of homocysteine may result from an inability to sustain S-NO formation owing to a progressive imbalance between the production of NO by progressively dysfunctional endothelial cells and the levels of homocysteine.
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PMID:Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. 838 Aug 12

Iron-derived reactive oxygen species are implicated in the pathogenesis of various vascular disorders including atherosclerosis, vasculitis, and reperfusion injury. The present studies examine whether heme, when liganded to physiologically relevant proteins as in hemoglobin, can provide potentially damaging iron to intact endothelium. We demonstrate that reduced ferrohemoglobin, while relatively innocuous to cultured endothelial cells, when oxidized to ferrihemoglobin (methemoglobin), greatly amplifies oxidant (H2O2)-mediated endothelial-cell injury. Drawing upon our previous observation that free heme similarly primes endothelium for oxidant damage, we posited that methemoglobin, but not ferrohemoglobin, releases its hemes that can then be incorporated into endothelial cells. In support, cultured endothelial cells exposed to methemoglobin--in contrast to exposure to ferrohemoglobin, cytochrome c, or metmyoglobin--rapidly increased their heme oxygenase mRNA and enzyme activity, thereby supporting heme uptake; ferritin production was also markedly increased after such exposure, thus attesting to eventual incorporation of Fe. These cellular methemoglobin effects were inhibited by the heme-scavenging protein hemopexin and by haptoglobin or cyanide, agents that strengthen the liganding between heme and globin. If the endothelium is exposed to methemoglobin for a more prolonged period (16 hr), it accumulates large amounts of ferritin; concomitantly, and presumably associated with iron sequestration by this protein, the endothelium converts from hypersusceptible to hyperresistant to oxidative damage. We conclude that when oxidation of hemoglobin facilitates release of its heme groups, catalytically active iron is provided to neighboring tissue environments. The effect of this relinquished heme on the vasculature is determined both by extracellular factors--i.e., plasma proteins, such as haptoglobin and hemopexin--as well as intracellular factors, including heme oxygenase and ferritin. Acutely, if both extra- and intracellular defenses are overwhelmed, cellular toxicity arises; chronically, when ferritin is induced, resistance to oxidative injury may supervene.
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PMID:Endothelial-cell heme uptake from heme proteins: induction of sensitization and desensitization to oxidant damage. 841 93

Oxidant injury of the vascular endothelium is considered an early event in the pathogenesis of atherosclerosis. In this study, the antioxidant effect of a 6-kDa thymic peptide (TP), isolated from calf thymus, was investigated in vitro using vascular endothelial cells. Confluent monolayers of bovine pulmonary artery endothelial cells (PAEC) were preincubated with different concentrations of TP for 24 h, washed, and then exposed to hydrogen peroxide (H2O2) for 2 or 4 h. Cell injury was assessed by measuring cell viability with methylthiazol tetrazolium (MTT) assay, and by determining the release of intracellular lactate dehydrogenase (LDH). Lipid peroxidation products of PAEC were monitored as malondialdehyde (MDA) with a thiobarbituric acid fluorometric assay. H2O2 (120 or 240 microM) incubated with PAEC decreased cell viability, increased LDH release, and elevated MDA production. Preincubation of PAEC with TP (25-150 micrograms/ml) before H2O2 exposure significantly increased cell viability, decreased LDH release, and reduced MDA production. These results demonstrate that TP can protect vascular endothelial cells from oxidant injury. The data thus suggest that TP may be useful for the prevention and/or treatment of atherosclerosis, and further suggest that immune modulating agents may directly or indirectly influence the functions of vascular endothelium.
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PMID:Thymic peptide protects vascular endothelial cells from hydrogen peroxide-induced oxidant injury. 849 41


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