Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ligand affinity chromatography was used to identify receptors on platelets and two adherent cell lines, OV-CAR-4 and HBL-100, for the E8 fragment of murine laminin. A complex of two polypeptides (140 and 110 kDa nonreduced) was bound by the E8 affinity columns from all three cell types and was eluted with EDTA. This heterodimeric complex was identified as the alpha 6 beta 1 integrin by immunoprecipitation with specific antibodies against either the alpha 6 or the beta 1 subunit. The alpha 6 beta 1 integrin did not bind to an affinity column containing fragment P1 originating from a different part of murine laminin which, however, bound the alpha IIb beta 3 integrin from platelets. Furthermore, in immunofluorescence staining, the alpha 6 beta 1 integrin localizes in focal contacts of OVCAR-4 cells attached to laminin and E8 but not to fibronectin substrates. These results, combined with previous antibody inhibition studies, unequivocally identify the alpha 6 beta 1 integrin as a specific receptor for fragment E8. Affinity chromatography of OVCAR-4 and HBL-100 cells on a large pepsin fragment of laminin from human placenta yielded integrin alpha 3 beta 1. When alpha 3 beta 1 was removed from lysates of OVCAR-4 cells by preclearing with an alpha 3-specific monoclonal antibody, alpha 6 beta 1 was able to bind to human laminin as well. Integrin alpha 6 beta 1 on platelets which do not express alpha 3 beta 1 binds directly to human laminin. These results indicate that both alpha 3 beta 1 and alpha 6 beta 1 can act as receptors for human laminin and may interfere by steric hindrance. The alpha 6 beta 4 complex, which is strongly expressed on HBL-100 cells, did not bind to either mouse laminin fragment E8 or human laminin affinity columns.
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PMID:Isolation of alpha 6 beta 1 integrins from platelets and adherent cells by affinity chromatography on mouse laminin fragment E8 and human laminin pepsin fragment. 195 58

We wished to test the hypothesis of a connection existing between inducible nitric oxide (NO) synthesis and production of extracellular matrix proteins in endothelial cells (EC). We recently reported that the inducible-NO pathway contributes to cytokine-induced enhancement of tumor cell (TC) adhesion to cultured vascular endothelium, independent of changes in E-selectin expression on endothelial cells (EC). We now show that inducible NO-synthase is involved in enhancing fibronectin production by EC. Indeed, fibronectin synthesis and secretion increased both in the EA.hy926 EC line and in human umbilical vein EC (HUVEC) after prolonged exposure to tumor necrosis factor-alpha (TNF-alpha) or interferon-gamma (IFN-gamma). This effect was reversed by the reported inhibitor of NO synthase N omega-nitro-L-arginine methyl ester (L-NAME 10(-5) M). The two cytokines exerted no additive effect, suggesting that they trigger a common metabolic pathway. NO production by cytokine-stimulated EC was dependent on the inducible NO-pathway, as demonstrated by studies of EC-dependent inhibition of platelet aggregation. This inhibition was also evident in calcium-free medium and was reversed by L-NAME and by two inhibitors of protein synthesis that are reported to block the inducible-NO synthase, such as dexamethasone (Dex 10(-7) M) and cycloheximide (Chx 10(-6) M). We conclude that modulation of the inducible NO-synthase may regulate matrix protein production by vascular endothelium during inflammation.
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PMID:Inducible nitric oxide synthase modulates fibronectin production in the EA.hy926 cell line and cultured human umbilical vein endothelial cells. 753 52

Elevations in plasma angiotensin II (AngII) are associated with an efflux of plasma macromolecules into the perivascular and contiguous interstitial space. Whether this exudative response is related to associated hypertension or another effect of AngII is uncertain. We therefore monitored plasma and cardiac lymph total protein, albumin and fibronectin and calculated transvascular clearances for total protein (TVPC) and albumin (TVAC) and lymph fibronectin transport (LFT) every 30 min in open-chested, instrumented dogs. After baseline observations were obtained over 30 min, pressor (250 ng.kg.min-1) or nonpressor (11 ng.kg.min-1) doses of AngII were given intravenously for 90 min. Saline-treated, instrumented dogs served as controls. To address a potential secondary effect of AngII on vascular protein clearance, we monitored lymph prostaglandin E2 and cGMP (a marker of released nitric oxide, NO). At > or = 30 min, each dose of AngII was associated with a significant (P < or = 0.05) and comparable increase in TVPC, TVAC and LFT over baseline, indicating that increase in protein clearance was not related to elevated arterial pressure. Lymph cGMP rose significantly (P < or = 0.05) at 30 min for each dose of AngII and remained elevated thereafter. Lymph PGE2 was increased at > or = 60 min (P < or = 0.05) but only with the pressor dose. To determine the contribution of NO and PGE2 on AngII-induced transcoronary protein clearance, each dose of AngII was accompanied by co-administration of either the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), or the cyclo-oxygenase inhibitor, indomethacin. L-NAME completely inhibited the release of cGMP and the increase in protein clearance was not seen. Indomethacin suppressed the release of PGE2, but did not prevent the increase in protein clearance. Thus, AngII-induced increase in transcoronary protein clearance is not related to arterial hypertension or the release of PGE2, but instead appears to be mediated by NO release.
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PMID:Angiotensin-II-induced increase in transcoronary protein clearance: role of hypertension vs. nitric oxide or cyclo-oxygenase products. 758 17

These studies were performed to determine if the effects of angiotensin II infusion on the development of cardiac fibrosis could be modified by the chronic inhibition of nitric oxide synthase activity. NG-nitro-L-arginine-methyl ester (L-NAME) was administered to adult Wistar rats in drinking water (40 mg/kg per d). Although blood pressure was maintained at hypertensive levels after 2 wk, cardiac hypertrophy or fibrosis did not occur. Angiotensin II, given for 3 d at a dose which induced little or no blood pressure elevation and minimal if any fibrosis, caused significant fibrosis when given to a rat pretreated for 2 wk with L-NAME. This marked fibrosis did not occur if angiotensin II was given shortly after L-NAME treatment was begun or briefly after discontinuation of L-NAME. The fibrosis that occurred with combined treatment was characterized by increased immunodetectable fibronectin, the presence of inflammatory cells within interstitial and perivascular regions, and increased steady state mRNA levels for matrix genes and atrial natriuretic protein. The data indicated a regulatory role for nitric oxide in modulating the angiotensin II-induced cardiac fibrosis and suggest a potentially important autocrine or paracrine role for nitric oxide in fibroblast proliferation.
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PMID:Angiotensin II-induced cardiac fibrosis in the rat is increased by chronic inhibition of nitric oxide synthase. 759 36

Nitric oxide (NO) is an important effector molecule of the inflammatory response. It is synthesized by mesangial cells and has been proposed to contribute to glomerular injury in various disease states. We studied whether NO modulates extracellular matrix production in cultured rat mesangial cells. Stimulation of rat mesangial cell NO release with gamma-interferon and lipopolysaccharide resulted in reduced production of collagen (by 35%) fibronectin (by 48%) (P < 0.05). In contrast, laminin synthesis was enhanced two-fold by the same maneuver (P < 0.05). These changes were reversed by the addition of L-NAME, a selective inhibitor of inducible nitric oxide synthase. This is the first demonstration that NO regulates the synthesis of extracellular matrix by mesangial cells. The results indicate that increased renal production of NO in glomerular diseases may attenuate the production and accumulation of matrix proteins and limit the severity of glomerulosclerosis.
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PMID:Nitric oxide modulates the synthesis of extracellular matrix proteins in cultured rat mesangial cells. 785 53

Chronic nitric oxide inhibition exacerbates hypertension and nephrosclerosis in spontaneously hypertensive rats (SHRs). In this study, we determined whether angiotensin-converting enzyme (ACE) inhibition could prevent or reverse the systemic, renal, and glomerular hemodynamic alterations and the pathological changes of nephrosclerosis. Four groups of 20-week-old SHRs were studied: group 1, untreated controls; group 2, treated with N omega-nitro-L-arginine methyl ester (L-NAME, 50 mg/L for 3 weeks); group 3, L-NAME cotreated with quinapril (3 mg.kg-1.d-1 for 3 weeks); and group 4, L-NAME for 3 weeks followed by quinapril for 3 weeks (same doses). The results of this study demonstrated that both cotreatment (group 3) and posttreatment (group 4) with quinapril reduced mean arterial pressure (186 +/- 9 and 192 +/- 9 mm Hg, respectively, compared with group 2 SHRs, 221 +/- 5 mm Hg) and total peripheral resistance index associated with significant reductions in afferent and efferent arteriolar resistances; nephrosclerosis pathological scores; and urinary protein excretion (all at least P < .01). ACE inhibition also significantly increased stroke index, single-nephron glomerular filtration rate, and ultrafiltration coefficient compared with the L-NAME SHRs. Most notable were the findings that cotreatment with quinapril completely prevented the renal glomerular hemodynamic alterations with reduced glomerular capillary hydrostatic pressure and efferent arteriolar resistance compared with both the untreated and the L-NAME-treated SHRs (all at least P < .01). Posttreatment with quinapril also reversed the glomerular injury (subcapsular, -83%; juxtamedullary, -56%) and arteriolar (-87%) injury scores obtained from renal biopsy specimens (P < .005 and P < .0001, respectively). These changes were associated with decreased periarteriolar fibronectin and increased afferent arteriolar alpha-smooth muscle actin deposition (immunohistochemistry). These data, therefore, demonstrate that ACE inhibition not only prevents but also reverses L-NAME-exacerbated severe nephrosclerosis in SHRs, as indicated by improved systemic, renal, and glomerular hemodynamic changes, proteinuria, and histological alterations.
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PMID:ACE inhibition prevents and reverses L-NAME-exacerbated nephrosclerosis in spontaneously hypertensive rats. 856 38

We recently demonstrated that stimulation of inducible nitric oxide synthase (iNOS) activity reduced the accumulation of collagen and fibronectin in cultured rat mesangial cells. Therefore, we examined whether nitric oxide (NO) influenced the activity of a 72 kDa neutral matrix metalloproteinase by these cells in vitro. Enzyme activity was assessed in a biotin-avidin ELISA and by zymography. Exposure of mesangial cells to the cytokines, interferon (IFN)-gamma and lipopolysaccharide (LPS), increased gelatinolytic activity by 325 +/- 60% (P < 0.025). Co-incubation with 20 mM L-arginine caused a further increase in matrix metalloproteinase levels. Addition of L-NAME, an inhibitor of iNOS, reversed the IFN-gamma/LPS-induced rise in gelatinolytic activity. Incubation with the exogenous NO donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP), resulted in a dose dependent increase in metalloproteinase activity (P < 0.01). The NO-induced changes in metalloproteinase activity were also demonstrable by zymography. These data indicate that NO modulates the activity of a 72 kDa neutral matrix metalloproteinase and suggest that altered NO production may contribute to the development of glomerulosclerosis and tubulointerstitial fibrosis in chronic renal disease states.
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PMID:Nitric oxide stimulates the activity of a 72-kDa neutral matrix metalloproteinase in cultured rat mesangial cells. 857 77

The involvement of platelets in neovascularization was investigated in the matrigel tube formation assay, an in vitro model of angiogenesis. Platelets promoted the formation of capillary-like structures (expressed as relative tube area) number- and time-dependently. Relative tube area increased from 0.98+/-0.02 (n = 8) in the presence of 6.25 x 10(4), to 3.21+/-0.12 (n=8) in the presence of 10(6) platelets/well compared to 0.54+/-0.04 (n=8) in their absence. This increase was unaffected by acetyl salicylic acid (ASA), apyrase, and hirudin. Photographs from representative experiments, showed that platelets adhered along the differentiating endothelium. Addition of alpha-thrombin (0.1-1 i.u. ml(-1)), the nitric oxide (NO) donor sodium nitroprusside (SNP; 1-100 microM) or the NO synthase inhibitor, L-NG-arginine-methylester (L-NAME, 30-300 microM) to the assay, had no effect on tube formation compared to that seen with platelets alone. Neuraminidase (0.01 i.u./10(7) platelets), which strips sialic acid residues from membrane glycoproteins, abolished the promoting effect of platelets on tube formation. The relative tube area in the presence of neuraminidase-treated platelets was 0.81+/-0.03 (n = 8), in the presence of untreated platelets 1.69+/-0.09, P<0.001 (n=8) and in the absence of platelets, 0.80+/-0.04 (n=8). The tetrapeptide Arg-Gly-Asp-Ser (RGDS; 20-200 microM) which inhibits von Willebrand factor, fibrinogen and fibronectin-mediated adhesion, had no effect on the promoting effect of platelets on tube formation. These results indicate that platelets promote angiogenesis in vitro. This effect is largely independent from activation by alpha-thrombin, is not modified by manipulating NO and prostaglandin metabolism and proceeds possibly through adhesion of the platelets to the differentiating endothelium.
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PMID:Evidence that platelets promote tube formation by endothelial cells on matrigel. 986 54

We investigated the mechanisms of renal vascular wall thickening in a rat model of N-nitro L-arginine methyl ester (L-NAME)-induced hypertension. To separate the effects of L-NAME-induced hypertension from other effects of nitric oxide (NO) inhibition, we created two models of L-NAME-induced hypertension: both had the same blood pressure level but NO inhibition was moderate in one group (group M) and severe in the other (group S). Urinary excretion of nitrates and nitrites was lower in group S than in group M. Wall thickening and lipid deposition in renal vessels were significantly greater in group S than in groups M. Simple and multiple regression analyses indicated that renal vascular wall thickening was more strongly correlated with lipid deposition than with blood pressure. The number of vessels positive for staining with Sudan black B was negatively correlated with urinary NO excretion. Expression of fibronectin and transforming growth factor-beta was greater in the Sudan black B-positive than in the Sudan black B-negative vessels, suggesting that extracellular matrix production was increased in vessels with lipid deposition. Lipid deposition and increased production of extracellular matrix may contribute to renal vascular wall thickening in L-NAME-induced hypertension. Some mechanisms independent of hypertension play important roles in vascular wall thickening induced by NO inhibition.
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PMID:The contribution of nitric oxide to renal vascular wall thickening in rats with L-NAME-induced hypertension. 987 Jun 89

Morphological changes in the myocardium after left ventricular hypertrophy, due to chronic experimental hypertension, require an understanding of the quantitative relationship between myocyte and nonmyocyte compartments forming the structural framework of the myocardium. Hypertension was induced by long-term low-dosage inhibition of nitric oxide synthesis by NG-nitro-L-arginine methyl ester (L-NAME) in rats. L-NAME (12 mg/kg) was given to animals in water ad libitum during 15 weeks. After this period, systolic blood pressure increased almost 50% as compared with that in the control group. Morphological changes in control and L-NAME animals were investigated with stereology and immunohistochemistry. Comparing control and L-NAME animals, the surface density of myocytes decreased 73.7% while the mean cross-sectional area increased 97.6% in L-NAME rats. The volume density of myocytes decreased 45.9% and the volume density of the interstitium increased 71.7% in L-NAME rats. No stereological difference was found in blood vessels comparing the two groups. Remodeling of the cardiac interstitium occurred with increased deposition of both fibronectin and type III collagen. Fibronectin was seen in both early and latter responses to infarction while type III collagen was seen mainly in areas of incomplete healing among myocytes and around intramyocardial branches of the coronary arteries. The long-term low-dosage administration of an inhibitor of the NO synthase such as L-NAME causes myocyte hypertrophy and early interstitial and perivascular fibrosis without important quantitative changes in microcirculation.
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PMID:Stereology and immunohistochemistry of the myocardium in experimental hypertension: long-term and low-dosage administration of inhibitor of the nitric oxide synthesis. 987 25


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