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

Phagocyte-mediated oxidant damage to vascular endothelium is likely involved in various vasculopathies including atherosclerosis and pulmonary leak syndromes such as adult respiratory distress syndrome. We have shown that heme, a hydrophobic iron chelate, is rapidly incorporated into endothelial cells where, after as little as 1 h, it markedly aggravates cytotoxicity engendered by polymorphonuclear leukocyte oxidants or hydrogen peroxide (H2O2). In contrast, however, if cultured endothelial cells are briefly pulsed with heme and then allowed to incubate for a prolonged period (16 h), the cells become highly resistant to oxidant-mediated injury and to the accumulation of endothelial lipid peroxidation products. This protection is associated with the induction within 4 h of mRNAs for both heme oxygenase and ferritin. After 16 h heme oxygenase and ferritin have increased approximately 50-fold and 10-fold, respectively. Differential induction of these proteins determined that ferritin is probably the ultimate cytoprotectant. Ferritin inhibits oxidant-mediated cytolysis in direct relation to its intracellular concentration. Apoferritin, when added to cultured endothelial cells, is taken up in a dose-responsive manner and appears as cytoplasmic granules by immunofluorescence; in a similar dose-responsive manner, added apoferritin protects endothelial cells from oxidant-mediated cytolysis. Conversely, a site-directed mutant of ferritin (heavy chain Glu62----Lys; His65----Gly) which lacks ferroxidase activity and is deficient in iron sequestering capacity, is completely ineffectual as a cytoprotectant. We conclude that endothelium and perhaps other cell types may be protected from oxidant damage through the iron sequestrant, ferritin.
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PMID:Ferritin: a cytoprotective antioxidant strategem of endothelium. 151 45

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

Vascular cell adhesion molecule-1 (VCAM-1) and its counterreceptor, the integrin very late antigen-4 (VLA-4), have recently been identified in smooth muscle cells during intimal thickening in humans and in newly forming vessels during ontogeny in mice, respectively. We examined the coexpression of VCAM-1 and the alpha 4 integrin subunit in human smooth muscle cells. The expression of VCAM-1 and alpha 4 subunit were studied during development of the aorta. In the 10-week-old human fetal aorta, VCAM-1 and alpha 4 were strongly expressed in smooth muscle cells. Their expression was dramatically reduced within the 24th week of gestation and disappeared in the adult aortic media. However, smooth muscle cells from intimal atherosclerotic thickening of adult aorta reexpressed both VCAM-1 and alpha 4. In a culture model mimicking smooth muscle differentiation, VCAM-1 mRNA and protein and alpha 4 integrin protein were coexpressed with smooth muscle-specific variants of cytoskeletal and contractile proteins, smooth muscle myosin heavy chain, caldesmon heavy chain, and desmin. Treatment with antibodies against VCAM-1 or alpha 4 integrin subunit interfered with the mRNA induction of smooth muscle-specific markers of differentiation. These results in vitro, associated with the transitory expression of VCAM-1 and VLA-4 during vascular ontogeny and the atherosclerosis process, point to a possible role of VCAM-1 and VLA-4 in the induction of smooth muscle differentiation.
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PMID:The integrin very late antigen-4 is expressed in human smooth muscle cell. Involvement of alpha 4 and vascular cell adhesion molecule-1 during smooth muscle cell differentiation. 901 38

This study examines the role of L-selectin in monocyte adhesion to arterial endothelium, a key pathogenic event of atherosclerosis. Using a nonstatic (rotation) adhesion assay, we observed that monocyte binding to bovine aortic endothelium at 4 degrees C increased four to nine times upon endothelium activation with tumor necrosis factor (TNF)-alpha. mAb-blocking experiments demonstrated that L-selectin mediates a major part (64 +/- 18%) of monocyte attachment. Videomicroscopy experiments performed under flow indicated that monocytes abruptly halted on 8-h TNF-alpha-activated aortic endothelium, approximately 80% of monocyte attachment being mediated by L-selectin. Flow cytometric studies with a L-selectin/IgM heavy chain chimeric protein showed calcium-dependent L-selectin binding to cytokine-activated and, unexpectedly, unactivated aortic cells. Soluble L-selectin binding was completely inhibited by anti-L-selectin mAb or by aortic cell exposure to trypsin. Experiments with cycloheximide, chlorate, or neuraminidase showed that protein synthesis and sulfate groups, but not sialic acid residues, were essential for L-selectin counterreceptor function. Moreover, heparin lyases partially inhibited soluble L-selectin binding to cytokine-activated aortic cells, whereas a stronger inhibition was seen with unstimulated endothelial cells, suggesting that cytokine activation could induce the expression of additional ligand(s) for L-selectin, distinct from heparan sulfate proteoglycans. Under flow, endothelial cell treatment with heparinase inhibited by approximately 80% monocyte attachment to TNF-alpha-activated aortic endothelium, indicating a major role for heparan sulfate proteoglycans in monocyte-endothelial interactions. Thus, L-selectin mediates monocyte attachment to activated aortic endothelium, and heparan sulfate proteoglycans serve as arterial ligands for monocyte L-selectin.
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PMID:Monocyte adhesion to activated aortic endothelium: role of L-selectin and heparan sulfate proteoglycans. 904 58

Aberrant vascular smooth muscle cell (VSMC) hyperplasia is the hallmark of atherosclerosis and restenosis seen after vascular surgery. Heparin inhibits VSMC proliferation in animal models and in cell culture. To test our hypothesis that heparin mediates its antiproliferative effect by altering phosphorylation of key mitogenic signaling proteins in VSMC, we examined tyrosine phosphorylation of cellular proteins in quiescent VSMC stimulated with serum in the presence or absence of heparin. Western blot analysis with anti-phosphotyrosine antibodies shows that heparin specifically alters the tyrosine phosphorylation of only two proteins (42 kDa and 200 kDa). The 200 kDa protein (p200) is dephosphorylated within 2.5 min after heparin treatment with an IC50 that closely parallels the IC50 for growth inhibition. Studies using the tyrosine phosphatase inhibitor, sodium orthovanadate, indicate that heparin blocks p200 phosphorylation by inhibiting a kinase. Phosphorylation of p200 is not altered in heparin-resistant cells, supporting a role for p200 in mediating the antiproliferative effect of heparin. Purification and sequence analysis indicate that p200 exhibits very high homology to the heavy chain of nonmuscle myosin IIA. The 42 kDa protein, identified as mitogen activated protein kinase (MAPK), undergoes dephosphorylation within 15 min after heparin treatment, and this effect is also not seen in heparin-resistant cells. The identification of only two heparin-regulated tyrosine phosphoproteins suggests that they may be key mediators of the antiproliferative effect of heparin.
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PMID:Heparin rapidly and selectively regulates protein tyrosine phosphorylation in vascular smooth muscle cells. 1004 85

An augmented expression of mRNA for IgG light chain was demonstrated age-dependently on atheromatous lesions of the aorta in Watanabe heritable hyperlipidemic (WHHL) rabbits. The present study was designed to determine factors related to inflammation in human vessels excised during surgery. We detected IgG mRNAs using RT-PCR in human atherosclerotic lesions but not in human umbilical arteries which have no atheromatous lesions. To determine the clonality of IgGs, cDNAs encoding variable regions of IgG heavy chain were examined using RT-PCR. Atherosclerotic lesions had several subtypes of IgG gene families' suggesting the involvement of polyclonal B-cells. mRNAs of interleukins-6 (IL-6), -1alpha (IL-1alpha), and -1beta (IL-1beta) were also detected in the same samples. In summary, inflammatory reactions were present in the atherosclerosis lesion.
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PMID:Immunoglobulin in atherosclerotic lesions of human aorta. 1073 60

Vascular smooth muscle cells (SMCs) undergo phenotype change with the development of atherosclerosis. The phenotype changes of SMCs have been observed in various culture conditions, such as collagen-coated dishes. Here, we report the morphological and functional features of SMCs in a novel culture system using type I-collagen in a characteristic three-dimensional structure designated as honeycombs. The number of ribosome and mitochondria in SMCs cultured in honeycombs was one half or third of those cultured on collagen-coated plastic plates. DNA and protein synthesis of SMCs cultured in honeycombs were less than 1 and 30-40%, respectively, of those cultured on plastic plates. In addition, PDGF-BB did not increase the amount of DNA synthesis in SMCs in honeycombs. SMCs in honeycombs were shown to express several proteins, which are known to express in SMCs in medial layers of arteries. Particularly, caldesmon heavy chain was expressed in SMCs cultured in honeycombs, whereas not in those on plastic plates. Although focal adhesion kinase (FAK) was clearly detected in SMCs in honeycomb, the phosphotyrosine content of focal adhesion kin ase decreased in the process of culture. Immunoblot analysis showed dear different expression of ERK1 and ERK2 of mitogen-activated protein kinase in SMCs. SMCs in honeycombs expressed ERK2, more abundantly compared to ERK1, whereas SMCs in plates show the same levels of expressions for both proteins. Thus, the histological and functional feature of SMCs in the novel culture system is different from SMCs in plastic plates. The three-dimensional culture system described here may be indicating that cultured SMCs are able to express different proteins responding to the surrounding structures.
Atherosclerosis 2001 Oct
PMID:Histological and functional analysis of vascular smooth muscle cells in a novel culture system with honeycomb-like structure. 1158 16

Elevation of serum gamma-glutamyltransferase (GGT) activity is a risk factor for myocardial infarction and stroke. GGT activity can catalyze the oxidation of low-density lipoprotein (LDL), a process involved in the pathogenesis of atherosclerosis. Serum GGT is partially adsorbed onto circulating LDL, and catalytically active GGT has been found within atherosclerotic plaques, colocalizing with oxidized LDL and foam cells. We investigated the the nature of the LDL-associated GGT, the degree of correlation between total serum GGT levels and beta-lipoprotein (beta-LP)-associated GGT, and whether this association is altered in subjects with coronary artery disease (CAD). LDL-bound GGT showed an entire, amphiphilic heavy chain, but the association was easily lost during LDL purification by affinity chromatography. When the activity of GGT associated with polycation-precipitated beta-lipoproteins was assayed, an identical immunoreactive GGT was found in Western blot, and a statistically significant linear correlation was found between total serum GGT levels and the corresponding beta-LP-bound activities (p<0.0001) in controls and patients with CAD. Nevertheless, subjects with CAD presented a lower ratio of beta-LP-bound GGT to total serum GGT respect to controls (p<0.05) and healthy subjects with elevated serum GGT (p<0.01). In addition, a relative decrease of total serum GGT was observed in CAD subjects of older age as compared to younger ones (p<0.005).
Atherosclerosis 2006 May
PMID:Beta-lipoprotein- and LDL-associated serum gamma-glutamyltransferase in patients with coronary atherosclerosis. 1611 19

Up-regulation of the gap-junctional protein connexin43 (Cx43) in arterial smooth muscle cells (SMCs) features in response to injury and in atherosclerosis, in parallel with phenotypic transition to the synthetic state. TGF-beta1 is known to have a role in SMC differentiation and extracellular matrix (ECM) synthesis, key characteristics of phenotypic state. Here, we set out to examine the effects of TGF-beta1 on Cx43-gap junction expression in relation to SMC differentiation, ECM synthesis and growth. Cx43 expression was analysed by immunoconfocal microscopy and Western blotting in primary human aortic SMCs treated with TGF-beta1 over a 48-h period, with assessment of gap-junctional communication by cell-to-cell transfer of microinjected ethidium bromide. In parallel, synthetic activity was analysed by Northern blotting for ECM components alpha-1(I) and alpha1(III) procollagen transcripts, contractile differentiation was assessed by immunoconfocal microscopy and Western blotting of the markers smooth muscle alpha-actin, calponin and smooth muscle heavy chain isoform 1 (SM1), and growth was measured by BrdU incorporation. Our results demonstrate that TGF-beta1 significantly up-regulates Cx43 expression and intercellular communication, in concert with increased expression of alpha-actin, calponin and SM1. Concomitant with contractile protein expression, ECM synthesis was increased rather than decreased, TGF-beta1 inducing a significant up-regulation of both procollagen transcripts. These effects were independent of growth. We conclude that in human aortic SMCs, TGF-beta1 treatment leads to up-regulation of Cx43-mediated gap-junctional communication and increased synthetic activity yet, somewhat paradoxically, also enhanced contractile differentiation.
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PMID:Up-regulation of connexin43 correlates with increased synthetic activity and enhanced contractile differentiation in TGF-beta-treated human aortic smooth muscle cells. 1644 84

Multiple sclerosis (MS) is a common autoimmune neurodegenerative disease of unknown cause, which results in inflammation and plaques of demyelination in brain and eventual axonal degeneration. We report the novel presence of oxidized phosphatidylcholine [1-palmitoyl-2-(5'-oxo)valeryl-sn-glycero-3-phosphorylcholine (POVPC)], a lipid associated with inflammatory diseases such as atherosclerosis and lung disease, in the brain of MS patients. The OxPC epitope was detected by Western blotting with the E06 monoclonal antibody. E06-positive lipid was present in the highest amounts in MS plaques, which also showed evidence of low-molecular-weight (15-kDa) OxPC-modified protein. E06 reactivity did not change with post-mortem interval, and E06-positive lipids were largely absent from control tissue. We then used a second monoclonal antibody (AB1-2, which recognizes the E06/T15 idiotype and therefore detects the presence of antibody to OxPC) to show that MS brain samples were strongly positive for the 50-kDa antibody heavy chain. We also showed that isoelectric focussing of the oligoclonal IgG characteristic of MS revealed some immunoglobulin bands that Western blotted with the AB1-2 antibody. Spinal cords from mice induced to undergo experimental allergic encephalomyelitis (EAE) also showed strong AB1-2 reactivity by both immunocytochemistry and Western blot analysis. We therefore conclude that we can detect both OxPC and 15-kDa protein modified by OxPC and the antibody to the antibody to OxPC (antiidiotype) in pathological tissue and suggest that this could play a role in the progression of MS.
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PMID:Oxidized phosphatidylcholine is a marker for neuroinflammation in multiple sclerosis brain. 1730 73


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