Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported that platelets release a soluble factor that decreases the solute permeability of cultured bovine aortic endothelial monolayers. This factor was characterized as heat stable, tryspsin sensitive, and not serotonin, adenosine, ADP, or ATP [F. R. Haselton and J. S. Alexander. Am. J. Physiol. 263 (Lung Cell Mol. Physiol. 7): L670-L678, 1992]. We now report its identity as lysophosphatidic acid (LPA). Endothelial permeability decreases rapidly, reversibly, and repeatedly when exposed to platelet supernatants. Continuous exposure produces a sustained decrease in permeability. Methanol extracts of platelet supernatants also decrease endothelial permeability. Treatment of methanol extracts of platelet supernatants with phospholipase B or alkaline phosphatase, which modify the structure of LPA, abolishes the permeability-decreasing activity. However, activity is unaffected by treatment with phospholipase A2. This pattern of enzyme inactivation is consistent with the structure of LPA. Furthermore, synthetic 1-oleoyl-LPA rapidly and significantly decreases endothelial permeability in a concentration-dependent manner. Platelet activation does not appear to be required to produce activity in supernatants from platelet isolations, since P-selectin expression is not increased and thromboxane B2 is < 14 pg/6,000 platelets. Our data show that platelets release a methanol-extractable compound with an enzyme degradation profile consistent with LPA, which decreases the permeability of endothelial monolayers in vitro. In vivo, LPA derived from platelets may be an important mediator of the transport barrier formed by the vascular endothelium.
 ...
PMID:Platelet-derived lysophosphatidic acid decreases endothelial permeability in vitro. 945 59

Recent studies suggest that increased vascular cell adhesion molecule-1 (VCAM-1) expression on vascular endothelium in bronchial mucosa biopsies correlates with interleukin-4 (IL-4) levels in bronchiolar lavage fluid of allergic asthmatics. The severity of asthma in patients allergic to house dust mite has also been shown to correlate with lipopolysaccharide (LPS), rather than allergen, concentration in dust. We hypothesized that to induce effective VCAM-1 expression in human lung microvascular endothelial cells (HLMVEC), IL-4 may require the presence of a co-stimulus such as LPS. To test this hypothesis we measured, by enzyme-linked immunosorbent assay, induction of cell adhesion molecule expression on, and human eosinophil adhesion to, cultured HLMVEC monolayers pretreated with IL-4 alone or combined with LPS. IL-4 synergized with LPS to induce VCAM-1 expression at 24, 48, or 72 h, whereas IL-4 alone induced expression at 72 h only. IL-4 did not induce expression of intercellular adhesion molecule-1 or E-selectin or alter LPS-induced expression of either. Pre-exposure of HLMVEC to LPS or IL-4 (1 h), followed by IL-4 or LPS, respectively (23 h), also induced VCAM-1 expression. Eosinophil adhesion to HLMVEC monolayers treated with IL-4 and LPS together, but not alone, significantly (P < 0.001) increased from 9.6 +/- 1.5% (control) to 26.9 +/- 3.3% and was inhibited by a monoclonal antibody against the VCAM-1 ligand, very late antigen-4. Analysis of VCAM-1 mRNA revealed synergism between IL-4 and LPS which may, in part, contribute to enhanced VCAM-1 expression. These results suggest that the presence of a co-stimulus such as LPS may be necessary for IL-4 to effectively induce VCAM-1 expression in lung microvasculature.
Am J Respir Cell Mol Biol 1998 May
PMID:Interleukin-4 and lipopolysaccharide synergize to induce vascular cell adhesion molecule-1 expression in human lung microvascular endothelial cells. 956 32

Reactive oxygen species (ROS) play an important role in the damage of vascular endothelium during atherogenesis and impaired endothelium-dependent vasorelaxation. We have studied the effect of two ROS generators (H2O2 and menadione) and one of the most potent antioxidants (morin) on the double immunofluorescent staining of endothelial cells (EC) from both Watanabe Heritable Hyperlipidemic (WHHL) and New Zealand White (NZW) rabbits in primary cultures using antibodies against endothelin-1 (ET-1), endothelial (eNOS), and inducible nitric oxide synthase (iNOS). In aortic EC from normal rabbits, ROS decreased the immunoreactivity of eNOS and ET-1 and this effect was significantly reversed by morin. In atherosclerotic rabbits, ROS had the same effect on the immunoreactivity of eNOS and ET-1 but also induced the expression of iNOS immunoreactivity. In general, the cells from WHHL rabbits were less sensitive to the protective effects of morin and more sensitive to the effects of ROS. It thus appears that the protective effect of morin may be due to neutralization of ROS and may be considered for the treatment of early stages of atherosclerosis, before macroscopic lesions have occurred.
Mol Genet Metab 1998 Mar
PMID:Free radical generators cause changes in endothelial and inducible nitric oxide synthases and endothelin-1 immunoreactivity in endothelial cells from hyperlipidemic rabbits. 960 41

The terminal event in the establishment of the haemochorial placenta in the human is the invasion of trophoblasts into the maternal vessels, a process in which trophoblasts interact directly with the vascular endothelium and degrade the vascular basement membrane and the tunica elastica of the vessels. To further understand this heterotypic cellular interaction, we investigated the expression by human trophoblasts of the vascular cell adhesion molecule platelet-endothelial cell adhesion molecule-1 (PECAM-1) as a possible mediator of the adhesive interaction between trophoblasts and endothelium. In vitro, human trophoblasts were found to express PECAM-1 mRNA and protein. Indirect immunofluorescence indicated a diffuse staining pattern, which was most intense in a subpopulation of trophoblast cells. Co-incubation of trophoblasts with endothelial cells showed interaction between these two cell types with strong expression of PECAM-1 at points of trophoblast-endothelial cell contact, suggesting that this cell adhesion molecule participates in this heterotypic cell interaction. Immunohistochemical localization of PECAM-1 in chorionic villi and first trimester implantation sites showed that, in vivo, only extravillous interstitial and endovascular trophoblasts were positive. In first trimester placentae, villous trophoblast and extravillous trophoblast in other locations than around or within the decidual vessels did not express this molecule. In term placentae, villous trophoblast did not express these adhesion molecules except for two specimens examined. This study demonstrates that PECAM-1 is expressed by a subset of human trophoblasts in vitro and in vivo. Its tissue localization suggests that PECAM-1 is important in mediating the adhesive interaction between trophoblasts and maternal vascular endothelium during the process of haemochorial placentation. Regulation of PECAM-1 expression by human trophoblasts may play a critical role in normal and abnormal vascular invasion during implantation and placentation.
Mol Hum Reprod 1998 Apr
PMID:Platelet-endothelial cell adhesion molecule-1 is expressed by a subpopulation of human trophoblasts: a possible mechanism for trophoblast-endothelial interaction during haemochorial placentation. 962 Aug 36

Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are members of the immunoglobulin superfamily adhesion molecules on vascular endothelium and important in the development of eosinophil (EOS) accumulation in allergic inflammation. To define the role of these adhesion proteins in EOS inflammation, peripheral blood EOS from allergic donors were incubated in either buffer (control)-, recombinant human (rh)-VCAM-1-, or rh-ICAM-1-coated plates, and the effects of these adhesion proteins on EOS effector functions were determined. VCAM-1 induced spontaneous EOS adhesion whereas EOS adhesion to ICAM-1 required a second signal, such as granulocyte macrophage colony-stimulating factor (GM-CSF). Although only VCAM-1 stimulated EOS superoxide anion (O2-) generation, the addition of GM-CSF (100 pM) to the reactions resulted in a greater and equivalent production of O2- with VCAM-1 and ICAM-1. In the presence of GM-CSF, ICAM-1 and VCAM-1 caused significant release of EOS-derived neurotoxin (EDN). Moreover, only ICAM-1 (no GM-CSF) promoted calcium ionophore A23187 (0.2 microM)-induced EOS leukotriene C4 (LTC4). Enhanced O2- generation, EDN release, and LTC4 generation observed with ICAM-1 and VCAM-1 were significantly inhibited by anti-beta2-integrin antibody. These results suggest that ICAM-1 and VCAM-1 are important in determining the eventual function of airway EOS.
Am J Respir Cell Mol Biol 1998 Jul
PMID:Granulocyte macrophage colony-stimulating factor augments ICAM-1 and VCAM-1 activation of eosinophil function. 965 Nov 92

During falciparum malaria infection, severe complications ensue because parasitized red blood cells (PRBCs) adhere to endothelial cells and accumulate in the microvasculature. At the molecular level, adhesion is mediated by interaction of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP-1) on the PRBC surface with receptors on the surface of endothelial cells, including CD36. We have shown that a recombinant 179-residue subfragment of PfEMP-1 (rC1-2[1-179]), which encompasses the CD36-binding region, inhibits and reverses adhesion of PRBCs to CD36 under physiologically relevant flow conditions. rC1-2[1-179] inhibited adhesion in a concentration-dependent manner over the range 100 pM to 2 microM, with up to 99% of adhesion blocked at the highest concentration tested. The antiadhesive activity of rC1-2[1-179] was not strain specific and almost totally ablated adhesion of four different parasite lines. Furthermore, rC1-2[1-179] showed remarkable ability to progressively reverse adhesion when flowed over adherent PRBCs for 2h. The effect of rC1-2[1-179] was, however, specific for CD36-mediated adhesion and had no effect on adhesion mediated by CSA. Interference with binding of PRBCs to the vascular endothelium using rC1-2[1-179] or smaller organic mimetics may be a useful therapeutic approach to ameliorate severe complications of falciparum malaria.
Mol Microbiol 1998 Oct
PMID:A recombinant peptide based on PfEMP-1 blocks and reverses adhesion of malaria-infected red blood cells to CD36 under flow. 978 87

The following is a review of an emerging topic in the literature which has led to new hypotheses regarding the mechanisms of pathogenesis of the various tissue specific AIDS associated syndromes. The fundamental hypothesis in this review proposes that HIV-1 is able to increase lymphocyte and monocyte localization in tissues where released HIV-1 proteins cause local tissue damage leading to any one of the various AIDS associated syndromes. It is also hypothesized here that syndromes associated with other lymphotrophic viruses result from the ability of these viruses to direct leukocyte extravasation of blood vessel walls and to initiate tissue specific pathogenesis. Further, it is suggested here that new concepts and strategies for delivering gene therapy to specific tissues can be derived from our understanding of the mechanisms through which lymphotrophic viruses localize in specific tissues. HIV-1 infection of lymphocytes and monocytes leads to increased adhesion of these cells to vascular endothelium and extracellular matrix molecules. In addition, HIV-1 infection of various leukocytes leads to increased secretion of extracellular matrix degrading matrix metalloproteinases. Increases in leukocyte adhesion and matrix metalloproteinase secretion are associated with the normal mechanisms through which leukocytes localize in tissues during inflammation. The ability of HIV-1 to activate leukocyte adhesion and matrix metalloproteinase secretion suggests that HIV-1 has evolved a way to take advantage of leukocyte inflammatory mechanisms in order to exit the blood stream and gain access to body tissues. The ability of HIV-1 to use infected cells to localize in various tissues may lead to the establishment of HIV-1 reservoirs in tissues. Such viral reservoirs may cause the various tissue specific AIDS associated syndromes. AIDS patients have been found to have elevated adhesion molecules (integrins, and cell adhesion molecules or CAMs) on their peripheral blood lymphocytes (PBLs). While there is little clinical evidence that the tissue localization of HIV-1 infected leukocytes are the cause of the HIV-1 related syndromes, studies in vitro and with animal models have shown that the HIV-1 gene products Tat, Rev and gp120 are potent neurotoxins. It has also been shown that Tat can contribute to the growth of cells from Kaposi's sarcoma lesions. Further, HIV-1 infected cells have been shown to secrete cytotoxic levels of a variety of growth factors and small molecules. Thus, it is likely that the localization of HIV-1 infected cells in specific tissues could contribute to the HIV-1 associated syndromes such as AIDS dementia, HIV-1 related interstitial lung disease, HIV-1 associated nephropathy, the HIV-1 wasting syndrome and perhaps AIDS associated Kaposi's sarcoma and hyperproliferative skin disorders. This review will examine studies in the literature which demonstrate that HIV-1 infection increases leukocyte adhesion and matrix metalloproteinase secretion. Clinical reports of AIDS patient's leukocyte integrin levels will also be reviewed and evidence that tissue localized HIV-1 infected cells could contribute to a variety of HIV-1 associated syndromes will be presented.
Int J Mol Med 1998 Feb
PMID:The role of HIV-1 activated leukocyte adhesion mechanisms and matrix metalloproteinase secretion in AIDS pathogenesis (Review). 985 38

Two isoforms of cyclo-oxygenase (COX) have been identified; a constitutive isoform (COX-1), found in abundance in platelets and the vascular endothelium, considered important for the roles of prostanoids and a cytokine/mitogen inducible isoform (COX-2), which is thought responsible for the majority of the inflammatory prostanoid production. As a number of COX metabolites regulate vascular smooth muscle cell function and the interaction between the vessel and circulating components, we have discussed the possibility that COX-2 can be induced in, and regulate human arterial or venous smooth muscle cell function. It is now clear that COX-2 can be induced in freshly isolated vessels in culture, which can be further stimulated by addition of pro-inflammatory cytokines. Interestingly, smooth muscle cells derived from saphenous vein can release extremely high levels of prostanoids, and express greater levels of COX-2 protein than internal mammary artery cells. This difference can be accounted for by an arterial cell-specific negative feedback mechanism. In addition to inducing COX-2, certain cytokines regulate smooth muscle function, by regulating cell proliferation, adhesion, and mediator release. The effects of COX-2 activity on these smooth muscle cell responses will be further discussed.
Int J Mol Med 1999 Jan
PMID:Cyclo-oxygenase-2 in vascular smooth muscle. 986 84

Cadherins are cell-cell adhesion receptors whose adhesive function requires their association with the actin cytoskeleton via proteins called catenins. The small guanosine triphosphatases (GTPases), Rho and Rac, are intracellular proteins that regulate the formation of distinct actin structures in different cell types. In keratinocytes and in other epithelial cells, Rho and Rac activities are required for E-cadherin function. Here we show that the regulation of cadherin adhesiveness by the small GTPases is influenced by the maturation status of the junction and the cellular context. E-cadherin localization was disrupted in mature keratinocyte junctions after inhibition of Rho and Rac. However, an incubation of 2 h was required after GTPase inhibition, when compared with newly established E-cadherin contacts (30 min). Regarding other cadherin receptors, P-cadherin was effectively removed from mature keratinocytes junctions by blocking Rho or Rac. In contrast, VE-cadherin localization at endothelial junctions was independent of Rho/Rac activity. We demontrate that the insensitivity of VE-cadherin to inhibition of Rho and Rac was not due to the maturation status of endothelial junction, but rather the cellular background: when transfected into CHO cells, the localization of VE-cadherin was perturbed by inhibition of Rho proteins. Our results suggest that the same stimuli may have different activity in regulating the paracellular activity in endothelial and epithelial cells. In addition, we uncovered possible roles for the small GTPases during the establishment of E-cadherin-dependent contacts. In keratinocytes, Rac activation by itself cannot promote accumulation of actin at the cell periphery in the absence of cadherin-dependent contacts. Moreover, neither Rho nor Rac activation was sufficient to redistribute cadherin molecules to cell borders, indicating that redistribution results mostly from the homophilic binding of the receptors. Our results point out the complexity of the regulation of cadherin-mediated adhesion by the small GTPases, Rho and Rac.
Mol Biol Cell 1999 Jan
PMID:Regulation of cadherin function by Rho and Rac: modulation by junction maturation and cellular context. 988 Mar 23

Selected dietary lipids may increase the atherogenicity of environmental chemicals, such as polychlorinated biphenyls (PCBs), by cross-amplifying mechanisms leading to dysfunction of the vascular endothelium. To investigate this hypothesis, cultured endothelial cells were treated with 90 microM linoleic acid (18:2n-6), followed by either one of two PCBs, 3,3',4,4'-tetrachlorobiphenyl (PCB 77) or 2,2'4,4',5,5'-hexachlorobiphenyl (PCB 153). These PCBs were selected for their varying binding activities with the aryl hydrocarbon (Ah) receptor and differences in their induction of cytochrome P450. PCB 77 disrupted endothelial barrier function by allowing an increase in albumin transfer across endothelial monolayers. Prior cellular enrichment with 18:2 before PCB treatment further diminished endothelial barrier function, as compared to cells treated only with the PCB. This phenomenon appears to be mediated by increased oxidative stress, which is supported by enhanced 2,7-dichlorofluorescein fluorescence, activation data of the oxidative stress-sensitive nuclear transcription factor-kappaB (NF-kappaB), as well as an observed decrease in vitamin E content in the culture media. Similar to the endothelial permeability data, pre-enrichment of cells with 18:2 further increased the PCB-mediated induction of cytochrome P450 1A. In contrast to PCB 77, PCB 153 (or 18:2 plus PCB 153) had little or no effect on endothelial barrier function. Our results suggest that certain unsaturated fatty acids can potentiate PCB-mediated endothelial cell dysfunction and that oxidative stress and activation of the cytochrome P450 1A subfamily may be, in part, responsible for these metabolic events. These findings have implications for understanding the involvement of certain environmental contaminants in diseases that involve dysfunction of the vascular endothelium.
J Biochem Mol Toxicol 1999
PMID:Linoleic acid amplifies polychlorinated biphenyl-mediated dysfunction of endothelial cells. 989 Jan 93


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>