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)

P-selectin (GMP-140) is an adhesion molecule present within endothelial cells that is rapidly translocated to the cell membrane upon activation, where it mediates endothelial-leukocyte interactions. Immunohistochemical analysis of human atherosclerotic plaques has shown strong expression of P-selectin by the endothelium overlying active atherosclerotic plaques. P-selectin is not, however, detected in normal arterial endothelium or in endothelium overlying inactive fibrous plaques. Color image analysis was used to quantitate the degree of P-selectin expression in the endothelium and demonstrates a statistically significant increase in P-selectin expression by atherosclerotic endothelial cells. Double immunofluorescence shows that some of this P-selectin is expressed on the luminal surface of the endothelial cells. Previous work has demonstrated a significant up-regulation in the expression of the intercellular adhesion molecule-1 in atherosclerotic endothelium and a study on the expression of intercellular adhesion molecule-1 and P-selectin in atherosclerosis shows a highly positive correlation. These results suggest that the selective and cooperative expression of P-selectin and intercellular adhesion molecule-1 may be involved in the recruitment of monocytes into sites of atherosclerosis.
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PMID:Increase in the adhesion molecule P-selectin in endothelium overlying atherosclerotic plaques. Coexpression with intercellular adhesion molecule-1. 751 51

We investigated the association between low-density lipoprotein (LDL), triglycerides, and platelet activation in 18 patients with hypertension age 41-64 years and 18 with diabetes mellitus aged 43-70 years. Platelet P-selectin positivity and the microparticle level (indicators of activation) were both significantly higher in the diabetics than in healthy controls (P-selectin: 28.0% +/- 7.5% vs. 7.3% +/- 4.2%, P < 0.001; microparticles: 1900 +/- 966 vs. 526 +/- 158/10(4) platelets, P < 0.01). In contrast, there was no significant increase of either parameter in the patients with hypertension. Plasma microparticle levels were also significantly greater in the diabetics with high LDL levels than in those with low LDL levels (2375 +/- 949 vs. 1519 +/- 796/10(4) platelets, P < 0.05), and in those with high rather than low triglyceride levels (2188 +/- 845 vs. 1492 +/- 783/10(4) platelets, P < 0.05). However, platelet positivity for P-selectin was not significantly different between these two subgroups. Microparticle and P-selectin levels both showed no significant difference between the hypertensive patients with high and low LDL or triglyceride levels. These results suggest that platelet-derived microparticles may participate in the development or progression of atherosclerosis in patients with diabetes mellitus.
Atherosclerosis 1995 Aug
PMID:Platelet-derived microparticles may influence the development of atherosclerosis in diabetes mellitus. 757 78

P-selectin is a transmembrane adhesion receptor specific to platelets and endothelial cells. It has an N-terminal lectin domain that recognizes specific carbohydrate moieties on monocytes, neutrophils and some other subsets of leukocytes. P-selectin is stored in granules and is expressed on the plasma membrane only after the cells are stimulated by vascular injury or during inflammation. Physiologically P-selectin is likely to be involved in the recruitment of leukocytes that promote wound healing and fight infection. There are many disorders in which the excessive recruitment of leukocytes is characteristic, including chronic inflammation, atherosclerosis, arthritis, diabetes, asthma and reperfusion injury. Because certain cancer cells also express the ligand for P-selectin it is possible that this receptor is involved in metastasis. To study the specific role of P-selectin in these pathological processes, we have prepared a mouse lacking P-selectin through gene targeting. Leukocyte interaction with the vessel wall is defective in these animals as leukocytes do not roll in the mesenteric venules and their extravasation at sites of inflammation and vessel injury is limited. We are testing these animals in models of the various diseases mentioned above in order to evaluate when the absence of P-selectin is beneficial.
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PMID:P-selectin knockout: a mouse model for various human diseases. 758 33

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

Platelets contain a vast number of biologically active molecules within cytoplasmic granules which are classified according to their respective distinct ultrastructures, densities and content. The alpha-granule is a unique secretory organelle in that it exhibits further compartmentalization and acquires its protein content via two distinct mechanisms: (1) biosynthesis predominantly at the megakaryocyte (MK) level (with some vestigial platelet synthesis) (e.g. platelet factor 4) and (2) endocytosis and pinocytosis at both the MK and circulating platelet levels (e.g. fibrinogen (Fg) and IgG). The currently known list of alpha-granular proteins continues to enlarge and includes many adhesive proteins (e.g. Fg, von Willebrand factor (vWf) and thrombospodin (TSP)), plasma proteins (e.g. IgG and albumin), cellular mitogens (e.g. platelet derived growth factor and TGF beta), coagulation factors (e.g. factor V) and protease inhibitors (e.g. alpha 2-macroglobulin and alpha 2-antiplasmin). More recently the inner lining of the alpha-granule unit membrane has been demonstrated to contain a number of physiologically important receptors including glycoprotein IIb/IIIa (alpha IIb beta 3) and P-selectin. The alpha-granules originate from small precursor granules which can be observed budding from the trans-Golgi network within the platelet precursor cell the MK. During MK maturation the alpha-granules become very prominent and are ultimately packaged into platelets during thrombopoiesis. The alpha-granular contents are destined for release during platelet activation at sites of vessel wall injury and thus play an important role in haemostasis, inflammation, ultimate wound repair and in the pathogenesis of atherosclerosis.
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PMID:Platelet alpha-granules. 846 33

Tissue plasminogen activator antigen (tPA), plasminogen activator inhibitor antigen (PAI-1), soluble P-selectin and von Willebrand factor antigen (vWf) were measured by ELISA in 41 patients with peripheral vascular disease (PVD), 41 with ischaemic heart disease (HD) and in 46 age and sex matched asymptomatic controls. Increased vWf was found in patients with IHD (p = 0.0002) and in patients with PVD (p = 0.0011) relative to the controls but levels did not differ between the two patients groups. Raised tPA found in both PVD (p = 0.0006) and IHD (p = 0.0061) compared to the controls also failed to differentiate the two groups of patients. Soluble P-selectin was also raised in both groups (p = 0.003 in IHD and p = 0.0102 in PVD) with no difference between the groups. There were no differences in levels of PAI-1 between the groups. In the subjects taken as a whole, there were significant Spearman's correlations between tPA and vWf (r = 0.37, p < 0.001), tPA and triglycerides (r = 0.38, p < 0.001), tPA and P-selectin (r = 0.19, p = 0.032), vWf and age (r = 0.25, p = 0.005) and inversely between vWf and HDL (r = -0.25, p = 0.006). These data support the concept that increased levels of tPA may be important in atherosclerosis, and indicate that soluble P-selectin may be useful in further analysis of the role of platelets and the endothelial cell in this disease.
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PMID:von Willebrand factor, soluble P-selectin, tissue plasminogen activator and plasminogen activator inhibitor in atherosclerosis. 858 97

Elevated levels of shear stress that occur in stenotic arteries may induce platelet aggregation and initiate thrombosis. Shear-induced platelet aggregation (SIPA) was studied in groups of ischemic stroke patients and normal subjects using a viscometric-flow cytometric technique. Twenty-three patients who sustained an ischemic stroke that was not of cardiac origin were included in this study, and were classified either as atherosclerotic (n = 15) or as lacunar (n = 8) stroke patients. The results show that shear stresses at the levels which occur in arteries partially occluded by atherosclerosis or vascular spasm strongly activate and aggregate platelets, and this response is much more pronounced in non-lacunar stroke patients who had documented atherosclerotic disease of their cerebral vessels. SIPA is not affected by the time of blood drawing after the onset of stroke suggesting that these platelet abnormalities are not transient but chronic. Furthermore, the extent of platelet activation detected by an anti-P-selectin monoclonal antibody and the proportion of neutrophil-platelet aggregates circulating in vivo are significantly higher in the atherosclerotic stroke patients studied at least one month after the onset of stroke. The results indicate that the enhanced platelet responses observed in atherosclerotic stroke patients are not consequences of ischemia, and therefore both platelet activation and elevated SIPA may be considered as important risk factors for stroke. The methodology developed in this work may be useful for characterization of platelet reactivity, and may contribute to our understanding of thrombotic mechanisms.
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PMID:Shear-induced platelet aggregation in normal subjects and stroke patients. 860 18

Lysophosphatidylcholine (LysoPC), an atherogenic lysophospholipid contained in oxidized low-density lipoprotein (LDL), has been shown to stimulate protein kinase C (PKC). Since PKC activators are suggested to elicit rapid P-selectin expression in platelets and endothelial cells, we examined whether LysoPc promotes P-selectin expression in platelets and P-selectin-mediated leukocyte adherence to endothelial cells via a mechanism involving PKC activation. LysoPc, but not phosphatidylcholine (PC), which is a major phospholipid component in native LDL, significantly upregulated P-selectin on cat platelets by flow cytometric analysis. This P-selectin upregulation by LysoPC was significantly attenuated by two PKC inhibitors, 7-hydroxystaurosporine (UCN-01) and N,N,N-trimethylsphingosine, and by two NO donors, CAS1609 and sodium nitroprusside. Submicellar concentrations of LysoPc significantly activated PKC in platelets, and this was inhibited by either UCN-01 or CAS1609. LysoPC, but not PC, significantly increased adherence of autologous cat polymorphonuclear leukocytes to coronary vascular endothelium, which was also markedly attenuated by UCN-01 and by CAS1609. LysoPC induced P-selectin expression on the surface of cat coronary vascular endothelium as assessed by immunohistochemical analysis. These results suggest that LysoPC, an atherogenic lysophospholipid contained in oxidized LDL, rapidly induces P-selectin expression in both platelets and endothelial cells at least partially via PKC activation. Furthermore, NO-generating agents may inhibit P-selectin upregulation by LysoPC. Since P-selectin may play an important role in initiating atherosclerosis, our data provide further insight into the mechanism of early stages of atherogenesis and of NO-mediated inhibition of atherosclerosis.
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PMID:Lysophosphatidylcholine promotes P-selectin expression in platelets and endothelial cells. Possible involvement of protein kinase C activation and its inhibition by nitric oxide donors. 862 May 97

Blood-derived macrophages in the arterial intima are a characteristic feature of active atherosclerotic plaques. Adherent monocytes on the luminal surface and increased adhesion molecules on the endothelium have suggested that specific molecular mechanisms are involved in monocyte/macrophage traffic into the arterial wall. Adhesion of human monocytes and related cell lines was therefore studied in vitro to histological sections of human plaques. At 37 degrees C, these cells bound selectively to the plaques. Binding to the endothelium occurred and was also present extensively in the diseased intima. Inhibition studies showed that the endothelial and general intimal binding had largely similar molecular properties. Strong inhibition was produced by antibodies to the monocyte-specific adhesion molecule CD14, to beta2 integrins, and to ICAM-1. Likewise, a peptide containing the Arg-Gly-Asp sequence was strongly inhibitory, suggesting that binding of leukocyte integrins to arterial extracellular matrix was synergistic with cell-cell interactions. A P-selectin antibody was exceptional in giving selective inhibition of endothelial adhesion, which correlates with the specific endothelial localization of this adhesion molecule. These results show that monocytes adhere to atherosclerotic plaques through the focal activation of multiple arterial wall adhesion molecules, confirming the adhesion hypothesis. A positive feedback theory for the pathogenesis of atherosclerosis can be suggested, based on the ability of macrophages in the wall to activate the endothelium, induce adhesion molecules, and facilitate additional monocyte entry. The adhesion assay provides a means for the identification of adhesion inhibitors with therapeutic potential.
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PMID:Localized adhesion of monocytes to human atherosclerotic plaques demonstrated in vitro: implications for atherogenesis. 868 64

Platelet activation in addition to blood coagulation abnormality is regarded as a primary factor of thrombosis by atherosclerotic obstruction. Therefore, the platelet activation on atherosclerosis is considered to correlate with shear stress generated between blood cells and endothelial cells in blood flow. P-selectin on the surface of the platelet membrane is measured by flowcytometry as a marker of platelet activation. Herein, we examined the phenomena of platelet activation and adherent platelets with leukocytes (ad-P.L) on stored platelet concentration (PC) and chronic rheumatoid arthritis (RA), moreover, of the adherent platelets or polymorphonuclear cells (PMN) with endothelial cells (EC) in shear stress by using an apparatus we devised. The rate of platelet activation and ad-P.L increased in PC with storage, and the sensitivity of platelets to thrombin decreased. The rate of platelet activation and ad-P.L increased in RA in vivo. Many adherent platelets with EC were found at a low shear rate on normal EC but at a high shear rate on denatured EC without any specific adherent property. Adherent PMN with EC had several hundred times more denatured EC than normal EC and the relationship with shear rate disappeared on denatured EC. The platelet activation and relationship between platelets or leukocytes and EC as to the cause of thrombosis are important subjects for future studies.
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PMID:[Adherent reaction among activated platelets, polymorphonuclear cells and vascular endothelial cells under thrombin stimulation or shear stress]. 881 62


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