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)

Flavonoids are reported to exhibit a wide variety of biological effects, including antioxidant and free radical-scavenging activities. Reactive oxygen species have been implicated in a range of human pathological diseases such as atherosclerosis and certain cancers. The aims of this present study were 1) to investigate the effect of the flavonoids myricetin, quercetin, and rutin on cell viability, endogenous antioxidant enzyme activities, and DNA integrity in Caco-2 and Hep G2 cells and 2) to determine whether these flavonoids could protect against H2O2-induced DNA damage. Both cell lines were supplemented with various concentrations (0-200 microM) of myricetin, quercetin, and rutin for 24 hours or H2O2 (50 microM) for 30 minutes, and cell viability was assessed. Over the concentration range tested, neither the flavonoids nor H2O2 significantly affected cell viability. The effect of the flavonoids on the activities of the antioxidant enzymes catalase (EC 1.11.1.6) and superoxide dismutase (EC 1.15.1.1) and on DNA integrity was assessed. The flavonoids did not significantly affect catalase or superoxide dismutase activity and did not induce DNA damage in either cell line. Exposure to 50 microM H2O2 for 30 minutes at 37 degrees C resulted in significant DNA damage, and preincubation with the flavonoids before H2O2 exposure significantly (p < 0.05) protected Caco-2 and Hep G2 cells against H2O2-induced DNA damage.
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PMID:Protection by the flavonoids myricetin, quercetin, and rutin against hydrogen peroxide-induced DNA damage in Caco-2 and Hep G2 cells. 1057 83

Multinucleated variant endothelial cells (MVECs) have frequently been observed in the human aorta, and the ratio of MVECs to typical endothelial cells correlates well with the severity of atherosclerosis. MVECs showed no capacity of proliferation in vitro, making their study extremely difficult. We attempted to obtain reproducible MVECs in vitro in order to understand their functional characteristics and their roles in atherosclerosis. This study was designed to derive MVECs from human umbilical cord vein endothelial cells (HUVECs) with different reagents such as Meso-4,4'-(2,3-butanediyl) bis (2,6-piperazinedione) (ICRF-193), low density lipoprotein (LDL), interleukin-4 (IL-4), polyethylene glycol (PG), H2O2, and linoleic acid hydroperoxide (LAHO). We found that 10 microM ICRF-193 was most effective in inducing MVECs. We then investigated the features of aortic endothelial cells (AECs) and ICRF-193 treated HUVECs (I-HUVECs) in the following four aspects: morphology, by light microscopy; cell cycle phase, by uptake of BrdU; expression of endothelial cell (EC) related markers such as von Willebrand Factor (vWF), endothelin-1 (ET-1), prostacyclin (PGI2) and intercellular adhesion molecule CD34 by immunocytochemistry; and biological activity by analyzing their uptake of low density lipoprotein (LDL). Furthermore, we compared aortic MVECs (AMVECs) and other aortic endothelial cells (A-others), as well as A-MVECs and ICRF-193 induced MVECs (I-MVECs) in every parameter examined. We found: 1. Compared with A-others, A-MVECs expressed more vWF (p < 0.01), more ET-1 (p < 0.05) and less CD34 (p < 0.01). In the uptake of LDL, A-MVECs took up more nLDL than A-others; 2. Both A-MVECs and I-MVECs contained multiple nuclei, but the nuclei differed in shape. A-MVECs and I-MVECs were similar in the nuclear incorporation of BrdU, in the uptake of nLDL and oxLDL, and in the expression of vWF, ET-1 and PGI2, but different in the expression of CD34 (p < 0.01). Our findings suggested that A-MVECs may transfer more plasma LDL to the subendothelial space because they took up more LDLs. I-MVECs were similar to A-MVECs morphologically and functionally. Thus, I-MVECs could be considered as substitutes in the study of A-MVECs.
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PMID:Formation of multinucleated variant endothelial cells in vitro and investigation of MVECs' features. 1059 8

To determine whether polymorphonuclear leukocytes (PMN) modulate the production of tissue factor (TF) by monocytes, PBMC were incubated with increasing concentrations of PMN. PMN did not express any procoagulant activity. After 20-h cocultures, PMN enhanced or inhibited the TF production of PBMC, and this effect depended on the PMN/PBMC ratio. When the ratio increased from 1/1000 to 1/5, without or with LPS, the TF activity of PBMC increased to peak at 2.5-fold the baseline value (p < 0.01). The TF Ag and TF mRNA also increased. This potentiating effect was mediated by reactive oxygen species (ROS) released by PMN during the coculture; it did not require direct cell contact between PMN and PBMC, it was enhanced when PMN were stimulated by fMLP (a chemotactic peptide), and it was inhibited by two antioxidants, N-acetyl cysteine and pyrrolidine dithiocarbamate. In contrast, when the PMN/PBMC ratio was further increased from 1/2 to 2/1, the PBMC TF activity, Ag, and mRNA decreased and were inhibited compared with those of PBMC cultured alone (p < 0.01). This inhibitory effect required direct cell contact between PMN and PBMC, and it was not due to a PMN-mediated cytotoxicity. To confirm the role of ROS, H2O2 enhanced then inhibited the TF activity of PBMC in a dose-dependent manner, similarly to PMN. Thus, PMN may play an important role in the pathogenesis of thrombosis and atherosclerosis by exerting concentration-dependent regulatory effects on the TF production by PBMC via the release of ROS.
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PMID:Polymorphonuclear leukocytes modulate tissue factor production by mononuclear cells: role of reactive oxygen species. 1072 43

Reactive oxygen species (ROS) such as the superoxide anion radical (O2.-) hydrogen peroxide (H2O2) and hydroxyl radical (.OH) have been implicated in the pathophysiology of various states, including ischemia reperfusion injury, haemorrhagic shock, atherosclerosis, heart failure, acute hypertension and cancer. The free radicals, nitric oxide (NO) and O2.- react to form peroxynitrite (ONOO-), a potent cytotoxic oxidant. A potential mechanism of oxidative damage is the nitration of tyrosine residues of protein, peroxidation of lipids, degradation of DNA and oligonucleosomal fragments. Several mechanisms are responsible for the protection of the cells from potential cytotoxic damage caused by free radicals. Cells have developed various enzymatic and nonenzymatic defense systems to control excited oxygen species, however, a certain fraction escapes the cellular defense and may cause permanent or transient damage to nucleic acids within the cells, leading to such events as DNA strand breakage and disruption of Ca2+ metabolism. There is currently great interest in the possible role of ROS in causing DNA damage that leads to cancer and spontaneous mutations. A high rate of oxidative damage to mammalian DNA has been demonstrated by measuring oxidized DNA bases excreted in urine after DNA repair. The rate of oxidative DNA damage is directly related to the metabolic rate and inversely related to life span of the organism.
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PMID:Reactive oxygen species and oxidative DNA damage. 1087 42

The 'oxidation theory' of atherosclerosis proposes that oxidation of low density lipoprotein (LDL) contributes to atherogenesis. Although the precise mechanisms of in vivo oxidation are widely unknown, increasing evidence suggests that myeloperoxidase (MPO, EC 1.11.1.7), a protein secreted by activated phagocytes, generates modified/oxidized (lipo)proteins via intermediate formation of hypochlorous acid (HOCl). In vitro generation of HOCl transforms lipoproteins into high uptake forms for macrophages giving rise to cholesterol-engorged foam cells. To identify HOCl-modified-epitopes in human plaque tissues we have raised monoclonal antibodies (directed against human HOCl-modified LDL) that do not cross-react with other LDL modifications, i.e. peroxynitrite-LDL, hemin-LDL, Cu2+-oxidized LDL, 4-hydroxynonenal-LDL, malondialdehyde-LDL, glycated-LDL, and acetylated-LDL. The antibodies recognized a specific epitope present on various proteins after treatment with OCl- added as reagent or generated by the MPO/H2O2/halide system. Immunohistochemical studies revealed pronounced staining for HOCl-modified-epitopes in fibroatheroma (type V) and complicated (type VI) lesions, while no staining was observed in aortae of lesion-prone location (type I). HOCl-oxidation-specific epitopes are detected in cells in the majority of atherosclerotic plaques but not in control segments. Staining was shown to be inside and outside monocytes/macrophages, endothelial cells, as well as in the extracellular matrix. A similar staining pattern using immunohistochemistry could be obtained for MPO. The colocalization of immunoreactive MPO and HOCl-modified-epitopes in serial sections of human atheroma (type IV), fibroatheroma (type V) and complicated (type VI) lesions provides further convincing evidence for MPO/H2O2/halide system-mediated oxidation of (lipo)proteins under in vivo conditions. We propose that MPO could act as an important link between the development of atherosclerotic plaque in the artery wall and chronic inflammatory events.
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PMID:Immunohistochemical evidence for the myeloperoxidase/H2O2/halide system in human atherosclerotic lesions: colocalization of myeloperoxidase and hypochlorite-modified proteins. 1088 Sep 73

Nitric oxide, a pivotal molecule in vascular homeostasis, is converted under aerobic conditions to nitrite. Recent studies have shown that myeloperoxidase (MPO), an abundant heme protein released by activated leukocytes, can oxidize nitrite (NO(2-)) to a radical species, most likely nitrogen dioxide. Furthermore, hypochlorous acid (HOCl), the major strong oxidant generated by MPO in the presence of physiological concentrations of chloride ions, can also react with nitrite, forming the reactive intermediate nitryl chloride. Since MPO and MPO-derived HOCl, as well as reactive nitrogen species, have been implicated in the pathogenesis of atherosclerosis through oxidative modification of low density lipoprotein (LDL), we investigated the effects of physiological concentrations of nitrite (12.5-200 microm) on MPO-mediated modification of LDL in the absence and presence of physiological chloride concentrations. Interestingly, nitrite concentrations as low as 12.5 and 25 microm significantly decreased MPO/H2O2)/Cl- -induced modification of apoB lysine residues, formation of N-chloramines, and increases in the relative electrophoretic mobility of LDL. In contrast, none of these markers of LDL atherogenic modification were affected by the MPO/H2O2/NO2-) system. Furthermore, experiments using ascorbate (12.5-200 microm) and the tyrosine analogue 4-hydroxyphenylacetic acid (12.5-200 microm), which are both substrates of MPO, indicated that nitrite inhibits MPO-mediated LDL modifications by trapping the enzyme in its inactive compound II form. These data offer a novel mechanism for a potential antiatherogenic effect of the nitric oxide congener nitrite.
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PMID:The nitric oxide congener nitrite inhibits myeloperoxidase/H2O2/ Cl- -mediated modification of low density lipoprotein. 1105 30

Elevated plasma levels of homocysteine have been identified as an important and independent risk factor for cerebral, coronary, and peripheral atherosclerosis, although the mechanisms are unclear. Homocysteine has been shown to promote cell proliferation and induction of the gene transcription factor c-fos in vascular smooth muscle cells. Earlier reports have suggested that homocysteine exert its effect via hydrogen peroxide (H2O2) produced during its metabolism. To evaluate the contribution of homocysteine to the pathogenesis of vascular diseases, we examined whether the effect of homocysteine on vascular smooth muscle cell growth is mediated by H2O2. We observed that 1.0 mM homocysteine induces DNA synthesis by 1.5-fold and proliferation of vascular smooth muscle cells two-fold in the presence of peroxide scavenging enzyme, catalase (2,600 U/ml). Our results suggest that homocysteine induces smooth muscle cell growth by an H2O2-independent pathway and that the effects of homocysteine may sum together with the known initiating events produced by oxidative stress and accelerate the progression of atherosclerosis.
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PMID:Homocysteine induces DNA synthesis and proliferation of vascular smooth muscle cells by a hydrogen peroxide-independent mechanism. 1122 47

Hydrogen peroxide and peroxynitrite induce relaxations via ATP-sensitive K+ channels, indicating that oxygen-derived free radicals may activate these channels. Levels of free radicals are increased throughout the arterial wall in animal models of atherosclerosis, and therefore, vasorelaxation via ATP-sensitive K+ channels may be augmented in chronic hypertension. The present study was designed to determine whether relaxations to an ATP-sensitive K+ channel opener, levcromakalim, are increased in the aorta from spontaneously hypertensive rats (SHR) and whether free radical scavengers reduce these relaxations. Rings of aortas without endothelium taken from age-matched Wistar-Kyoto rats (WKY) and SHR were suspended for isometric force recording. Relaxations to levcromakalim (10(-8) to 10(-5) M), which are abolished by glibenclamide (10(-5) M), were augmented in the aorta from SHR, compared to those in the aorta from WKY. In the aorta from SHR, catalase (1200 U/ml), but neither superoxide dismutase (150 U/ml) nor deferoxamine (10(-4) M), reduced relaxations to levcromakalim, whereas in the aorta from WKY, the free radical scavengers did not affect these relaxations. These results suggest that in chronic hypertension, vasorelaxation to an ATP-sensitive K+ channel opener is augmented and that hydrogen peroxide produced in smooth muscle cells may partly contribute to these relaxations.
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PMID:The role of oxygen-derived free radicals in augmented relaxations to levcromakalim in the aorta from hypertensive rats. 1124 71

Bed rest is an integral part of treatment of numerous diseases. Typical examples are bone fractures of lower extremities and pelvis. Temporary immobilization is necessary also, e.g., in heart diseases (stroke), backbone and imminent abortion. The sick organism spares energy during the bed rest wich is beneficial. However, bed rest results in many alterations which are disadavantageous. They concern the function of almost all organs and systems but affect most significantly the locomotor and ciruclatory systems. Bed rest brings also about changes in the composition of peripheral blood and functions of the morphotic elements of blood. Red blood cells are subjected to the action of large amounts of reactive oxygen species (ROS). During oxidation of hemoglobin to methemoglobin superoxide radical anion (O2-) is formed: HbFe2+ + O2 --> MetHbFe3+ + O2- (1) Ferrous and ferric ions present in the cytoplasm of red blood cells may be catalysts of the Fenton reaction leading to the production of the hydroxyl radical: O2- + Fe3+ --> O2- + Fe2+ (2) Fe2+ + H2O2 --> Fe3+ + OH + HO- (3) OH shows a tremendous reactivity. It may react with lipids, proteins, nucleic acids and carbohydrates. The process of lipid peroxidation is best understood. It concerns mainly polyunsaturated fatty acids present in cell membranes. Peroxidation of membrane lipids decreases membrane fluidity and impairs its barrier function. The lowered membrane fluidity compromises erythrocyte deormability which in turn disturbs oxygen delivery to the tissues. End productions of lipid peroxidation are low-molecular wieght compounds, among them carbohydrates (ethane and pentane) and aldehydes, e.g. malondialdehyde (MDA). MDA concentration is an acknowldeged marker of the intensity of lipid peroxidation. Erythrocytes contain a complex system of protection against the action of ROS. It includes various enzymatic and non-enzymatic mechanism. The most important antioxidative enzymes of the red blood cells are superoxide dismutase (Cu,Zn-SOD, EC 1.15.1.1) catalase (CAT, EC 1.11.1.6) and glutathione peroxidase (GSH-Px, EC 1.11.1.9). Cu,Zn-SOD catalyzes the dismuation of O2- to hydrogen peroxide (H2O2). Catalase and peroxidase remove H2O2 and, moreover, GSH-Px can reduce lipid peroxides. Under normal conditions an equilibrium exists between the formation and removal ROS. If ROS are formed in excess or the defensive antioxidative mechanism are inefficient, oxidative stress develops. Derangement of the equilibrium between the formation and removal of ROS is important in the pathosgenesis of many diseases, e.g. atherosclerosis, diabetes, Down syndrome and Alzheimer disease. There are literature data on disturbances of enzymatic antioxidant defense mechanism of blood plateless during bed rest. This study was aimed at an examination of the post-traumatic bed rest on the enzymatic antioxidative defense mechanisms and lipid peroxidation in erythrocytes.
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PMID:Effect of long term bed rest in men on enzymatic antioxidative defence and lipid peroxidation in erythrocytes. 1154 39

Optimal oxygen-dependent antimicrobial activity of circulating polymorphonuclear leukocytes reflects the synergistic effects of the myeloperoxidase (MPO)-hydrogen peroxide-halide system. Delivered from its storage compartment to the phagolysosome during fusion of the azurophilic granules, MPO catalyzes the oxidation of chloride in the presence of H2O2, chemistry unique to MPO, and thereby generates an array of highly reactive oxidants. Recent investigations of a wide range of inflammatory disorders have identified biochemical markers of MPO-dependent reactions, thus indirectly implicating MPO in their pathogenesis, progression, or perpetuation. The implied involvement of MPO-dependent events in diseases such as atherosclerosis forces reexamination of several fundamental tenets about MPO that are derived from studies of myeloid cells, most notably factors important in the regulated expression of MPO gene transcription. The evidence supporting a role for MPO in the pathogenesis of atherosclerosis, demyelinating diseases of the central nervous system, and specific cancers is reviewed and some of the new questions raised by these studies are discussed. Lastly, an appreciation for the existence of a broad family of proteins structurally related to MPO and the functional diversity implied by the corresponding structures may provide insights into novel ways in which MPO can function as more than an important antimicrobial component.
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PMID:Contributions of myeloperoxidase to proinflammatory events: more than an antimicrobial system. 1159 11

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