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)

We have previously reported that fibrinogen/fibrin can induce the migration of vascular smooth muscle cells in vitro. In this study, we examined the effect of substrate-bound fibrinogen/fibrin and other cell attachment-promoting proteins on the adhesion of vascular smooth muscle cells. The amount of fibrinogen/fibrin adsorbed to plastic wells and the adhesion of smooth muscle cells to the wells were found to depend on the concentration of fibrinogen used for coating the wells. The effect of fibrinogen/fibrin was comparable to that of so-called cell attachment-promoting proteins (fibronectin, vitronectin, and type I collagen). Adhesion of smooth muscle cells to fibrinogen/fibrin-coated wells was inhibited by the synthetic peptide GRGDS, but not by a control peptide, GRGES. Vitronectin, fibronectin, type I collagen, denatured type I collagen and commercial gelatin also induced smooth muscle cell adhesion. The adhesion induced by vitronectin, denatured type I collagen, and commercial gelatin was inhibited by GRGDS. However, the adhesion induced by type I collagen was not influenced and that induced by fibronectin was only slightly inhibited. These observations suggest that fibrinogen/fibrin deposited extracellularly in the arterial intima may act as a scaffold in the process of smooth muscle cell migration.
Atherosclerosis 1992 Oct
PMID:Substrate-bound fibrinogen, fibrin and other cell attachment-promoting proteins as a scaffold for cultured vascular smooth muscle cells. 128 31

We have isolated from a rabbit liver cDNA library, clones coding for the 66-kDa glycoprotein (GP66) characterized previously by EMR1a/212D monoclonal antibody (Nakagami, K., Shimasaki, O., Sato, R., Komine, Y., Ohkuma, S. and Takano, T. (1989) Am. J. Pathol. 135, 93-100), which recognizes the extracellular regions of atherosclerotic arterial wall. The clone spans the sequence coding for the entire GP66 (456 amino acids) and 19 amino acids of signal peptide. GP66 deduced from nucleotide sequence contained an Arg-Gly-Asp cell attachment sequence and had a 76% amino acid sequence homology with human vitronectin. Furthermore, EMR1a/212D recognized rabbit vitronectin purified by heparin-affinity chromatography. RNA blot hybridization detected one transcript of the same size in normal and Watanabe-heritable hyperlipidemic rabbit liver. The levels of plasma GP66 and liver GP66 mRNA were not altered, whereas 9-fold greater accumulation of GP66 was observed in thoracic aorta of Watanabe-heritable hyperlipidemic rabbit. These results suggest that GP66 is rabbit vitronectin and that it is vitronectin which selectively accumulates in thoracic aorta with the development of atherosclerosis.
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PMID:Monoclonal antibody EMR1a/212D recognizing site of deposition of extracellular lipid in atherosclerosis. Isolation and characterization of a cDNA clone for the antigen. 170 Nov 77

Vitronectin, a multifunctional glycoprotein present in the plasma and interstitial tissues, has recently been found to be localized in atherosclerotic lesions. In this study we examined the effects of vitronectin on the migration of cultured bovine aortic smooth muscle cells using a modified Boyden chamber assay. The cells migrated to fluid-phase vitronectin in a concentration-dependent fashion. The cells also migrated to membrane filter surfaces precoated with vitronectin for a few minutes in the absence of additional vitronectin in the fluid phase, suggesting that this substance binds easily to the filters and stimulates cell migration by haptotaxis under the conditions described. These observations suggest that vitronectin deposited in the intima may be involved in the pathogenesis of atherosclerosis by recruiting smooth muscle cells from the media into the intima.
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PMID:Vitronectin-induced haptotaxis of vascular smooth muscle cells in vitro. 170 22

Thrombin, in addition to its central role in hemostasis, possesses diverse cellular bioregulatory functions implicated in wound healing, inflammation, and atherosclerosis. In the present study we demonstrate that thrombin molecules modified either at the procoagulant or catalytic sites induce endothelial cell (EC) adhesion, spreading, and cytoskeletal reorganization. The most potent adhesive thrombin analogue (NO2-alpha-thrombin) was obtained by nitration of tyrosine residues. The cell adhesion promoting activity of NO2-alpha-thrombin was blocked upon the formation of thrombin-antithrombin III (ATIII) complexes and by antiprothrombin antibodies, but was unaffected by hirudin. Arg-Gly-Asp-containing peptides, fully inhibited EC adhesion to NO2-alpha-thrombin, while synthetic peptides corresponding to thrombin "Loop B" mitogenic site and the thrombin-derived chemotactic fragment "CB67-129", were uneffective. Immunofluorescence studies indicated that EC adhesion to NO2-alpha-thrombin was followed by cell spreading, actin microfilament assembly, and formation of focal contacts. By the use of specific antibodies, the vitronectin (vn) receptor (alpha v beta 3) was found to be localized in clusters upon cell adhesion to NO2-alpha-thrombin. An anti alpha v beta 3 antibody blocked EC adhesion and spreading while antifibronectin (fn) receptor (alpha 5 beta 1) antibodies were uneffective. While native thrombin exhibited a very low cell attachment activity, thrombin that was incubated at 37 degrees C before coating of plastic surfaces induced EC attachment and spreading. We propose that under certain conditions the naturally hindered RGD domain within thrombin is exposed for interaction with alpha v beta 3 on EC. This in turn promotes cell adhesion, spreading, and reorganization of cytoskeletal elements, which may altogether contribute to repair mechanisms in the disturbed vessel wall. This study defines a new biological role of thrombin and characterizes a new recognition mechanism on EC for this molecule.
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PMID:An Arg-Gly-Asp sequence within thrombin promotes endothelial cell adhesion. 198 65

Forty-nine regions in 21 proteins were identified as potential heparin-binding sites based on the sequence organizations of their basic and nonbasic residues. Twelve known heparin-binding sequences in vitronectin, apolipoproteins E and B-100, and platelet factor 4 were used to formulate two search strings for identifying potential heparin-binding regions in other proteins. Consensus sequences for glycosaminoglycan recognition were determined as [-X-B-B-X-B-X-] and [-X-B-B-B-X-X-B-X-] where B is the probability of a basic residue and X is a hydropathic residue. Predictions were then made as to the heparin-binding domains in endothelial cell growth factor, purpurin, and antithrombin-III. Many of the natural sequences conforming to these consensus motifs show prominent amphipathic periodicities having both alpha-helical and beta-strand conformations as determined by predictive algorithms and circular dichroism studies. The heparin-binding domain of vitronectin was modeled and formed a hydrophilic pocket that wrapped around and folded over a heparin octasaccharide, yielding a complementary structure. We suggest that these consensus sequence elements form potential nucleation sites for the recognition of polyanions in proteins and may provide a useful guide in identifying heparin-binding regions in other proteins. The possible relevance of protein-glycosaminoglycans interactions in atherosclerosis is discussed.
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PMID:Molecular modeling of protein-glycosaminoglycan interactions. 246 27

S-protein/vitronectin is a multifunctional glycoprotein interacting with both complement activation and coagulation pathways. Its presence was investigated in 5 femoral and 5 iliac atherosclerotic human arteries, obtained at surgery, by immunoelectron microscopy using an affinity purified rabbit IgG specific for human S-protein/vitronectin. The immunoelectron dense specific deposits were found in both intimal thickenings and fibrous plaques in association with elastic fibers, collagen bundles and cell debris in the vicinity of elastin. Cell debris embedded in the collagen matrix were S-protein/vitronectin negative. S-protein/vitronectin was also absent on intact cells, lipid droplets and cholesterol clefts. All cell debris, however, was positive for C5b-9 deposits suggesting that complement activation had occurred at these sites with or without S-protein/vitronectin interaction. S-protein/vitronectin may play a role in the arterial wall defence by restricting the extent of complement activation.
Atherosclerosis 1989 Aug
PMID:Immunoelectron-microscopic localization of S-protein/vitronectin in human atherosclerotic wall. 247 93

The terminal C5b-9 neoantigens of the complement complex, S-protein (Vitronectin), C3c, C3d and apolipoprotein B were localized on 16 aortic fibrous plaques, 8 aortic intimal thickenings, 4 fatty streaks intimae, 12 coronary fibrous plaques, 3 coronary intimal thickenings, 6 femoral and 5 basilar fibrous plaques, using an indirect and double-staining immunoperoxidase method. The granular specific deposits were localized in the fibrous cap and deeper parts of the plaque or in the deeper intima and inner-third media of intimal thickenings and fatty streaks intimae, in relation to the degree of atherosclerotic involvement. The different localization of C5b-9 and S-protein demonstrated by the double-staining technique is more suggestive for the assembly of the complex into the arterial wall and not for its preformed passage from circulation. The relation of these immune deposits to the degree of fibrosis and necrosis and their presence from the initial stages through to the advanced lesions could ascribe a role to the complement system in atherosclerosis.
Atherosclerosis 1987 May
PMID:Immunohistochemical localization of C5b-9, S-protein, C3d and apolipoprotein B in human arterial tissues with atherosclerosis. 295 91

Accumulation of plasminogen activator inhibitor type 1 (PAI-1) in the arterial wall may accelerate atherogenesis by inhibiting fibrinolysis, diminishing proteolysis of extracellular matrix proteins, or modifying migration of vascular smooth muscle cells. Increased intramural expression of the PAI-1 gene is induced by thrombosis. To determine whether it occurs also in response to a sustained mechanical insult to endothelium, hypercholesterolemia, or both, rabbits were subjected to sustained aortic injury induced by implantation of indwelling polyethylene tubing, to hyperlipidemia induced by cholesterol and peanut oil feeding over a period of 8 weeks, or both. Sustained vascular injury alone did not increase plasma PAI-1. However, hypercholesterolemia with or without mechanically induced vascular injury increased plasma PAI-1 twofold. The expression of PAI-1 mRNA in aorta (Northern blots) was significantly increased when vascular injury was combined with hyperlipidemia. In situ hybridization showed that the increase with mechanical injury alone occurred in endothelial cells covering the neointima (positive for factor VIII and thrombomodulin), in abnormally differentiated vascular smooth muscle cells (positive for embryonic myosin heavy chain), and in macrophages (positive for the RAM-11 anti-macrophage antibody). Qualitatively similar but much more marked increases in PAI-1 gene expression were seen when arterial injury was accompanied by hypercholesterolemia. Neither vitronectin, known to stabilize PAI-1, nor vitronectin mRNA increased in liver. However, immunocytochemistry and Western blots demonstrated marked aortic accumulation of vitronectin protein with hyperlipidemia, particularly in subendothelial fibrotic regions, accompanied by increased neointimal vitronectin mRNA as shown by in situ hybridization. These results suggest that increased synthesis and stabilization of vascular PAI-1 may potentiate accumulation of extracellular matrix, thereby accelerating atherosclerosis.
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PMID:Potentiation by hypercholesterolemia of the induction of aortic intramural synthesis of plasminogen activator inhibitor type 1 by endothelial injury. 769 Mar 10

Mammalian class A macrophage-specific scavenger receptors (SR-A) exhibit unusually broad binding specificity for a wide variety of polyanionic ligands. The properties of these receptors suggest that they may be involved in atherosclerosis and host defense. We have previously observed a similar receptor activity in Drosophila melanogaster embryonic macrophages and in the Drosophila macrophage-like Schneider L2 cell line. Expression cloning was used to isolate from L2 cells a cDNA that encodes a third class (class C) of scavenger receptor, Drosophila SR-CI (dSR-CI). dSR-CI expression was restricted to macrophages/hemocytes during embryonic development. When expressed in mammalian cells, dSR-CI exhibited high affinity and saturable binding of 125I-labeled acetylated low density lipoprotein and mediated its chloroquine-dependent, presumably lysosomal, degradation. Although the broad polyanionic ligand-binding specificity of dSR-CI was similar to that of SR-A, their predicted protein sequences are not similar. dSR-CI is a 609-residue type I integral membrane protein containing several well-known sequence motifs, including two complement control protein (CCP) domains and somatomedin B, MAM, and mucin-like domains. Macrophage scavenger receptors apparently mediate important, well-conserved functions and may be pattern-recognition receptors that arose early in the evolution of host-defense mechanisms. Genetic and physiologic analysis of dSR-CI function in Drosophila should provide further insights into the roles played by scavenger receptors in host defense and development.
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PMID:Expression cloning of dSR-CI, a class C macrophage-specific scavenger receptor from Drosophila melanogaster. 773 30

Although primarily recognized for its role in hemostasis, fibrinogen is also required for competent inflammatory reactions in vivo. It is now shown that fibrinogen promotes adhesion to and migration across an endothelial monolayer of terminally differentiated myelomonocytic cells. This process does not require chemotactic/haptotactic gradients or cytokine stimulation of the endothelium and is specific for the association of fibrinogen with intercellular adhesion molecule 1 (ICAM-1) on endothelium. Among other adhesive plasma proteins, fibronectin fails to increase the binding of leukocytes to endothelium, or transendothelial migration, whereas vitronectin promotes the binding but not the migration. The fibrinogen-mediated leukocyte adhesion and transendothelial migration could be inhibited by a peptide from the fibrinogen gamma-chain sequence N117NQKIVNL-KEKVAQLEA133, which blocks the binding of fibrinogen to ICAM-1. This interaction could also be inhibited by new anti-ICAM-1 monoclonal antibodies that did not affect the ICAM-1-CD11a/CD18 recognition, thus suggesting that the fibrinogen binding site on ICAM-1 may be structurally distinct from regions previously implicated in leukocyte-endothelium interaction. Therefore, binding of fibrinogen to vascular cell receptors is sufficient to initiate (i) increased leukocyte adhesion to endothelium and (ii) leukocyte transendothelial migration. These two processes are the earliest events of immune inflammatory responses and may also contribute to atherosclerosis.
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PMID:Regulation of leukocyte-endothelium interaction and leukocyte transendothelial migration by intercellular adhesion molecule 1-fibrinogen recognition. 787 9


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