Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the hypothesis that neutrophil (PMN)-mediated injury of the vascular endothelium is dependent on adhesion of PMNs to endothelial cells via the leukocyte adhesion glycoprotein CD11/CD18. We compared the PMN activation responses [i.e. adhesion to cultured endothelial cells, superoxide (O2-) production, degranulation, and cytosolic [Ca2+] ([Ca2+]i)] and endothelial injury elicited by opsonized zymosan (OZ, which is phagocytosed by PMNs) or phorbol 12-myristate 13-acetate (PMA, a protein kinase C activator). The basal adherence of nonstimulated PMNs to bovine pulmonary artery endothelial cells (BPAEC) was 9.0 +/- 1.1 PMN/field. PMA and OZ increased PMN adherence to BPAEC (to 31.1 +/- 1.4 and 39.8 +/- 3.8 PMN/field, respectively), which in both cases was inhibited by anti-CD18 monoclonal antibody (mAb) IB4. Stimulation of PMNs with PMA or OZ produced injury to 73% and 53% of BPAEC examined, respectively, which corresponded to 6.8-fold and 3.5-fold increases in transendothelial 125I-albumin permeability from baseline. Pretreatment of PMNs with mAb IB4 prevented endothelial injury in both cases. Both PMA and OZ increased the production of O2- (by 7.6-fold and 3.1-fold over control, respectively) and promoted the release of myeloperoxidase (5.2-fold and 9.1-fold over control, respectively) (P < .01). IB4 did not inhibit the PMA- or OZ-induced increases in O2-. IB4 did not inhibit the PMA-induced myeloperoxidase release but reduced by approximately 29% the OZ-induced myeloperoxidase release. Stimulation of PMNs layered on BPAEC with OZ (0.5 mg/ml) caused an approximately 7-fold increase in PMN [Ca2+]i over baseline, which decayed to a steady-state level above baseline at 10 min. IB4 (10 micrograms/ml) alone did not alter baseline [Ca2+]i and did not inhibit the OZ-induced increase in [Ca2+]i. In contrast to OZ, stimulation of PMNs with PMA did not increase [Ca2+]i. The results indicate that the protective effects of the anti-CD18 mAb IB4 were associated predominantly with its antiadherence property. Therefore, CD18 integrin-mediated PMN adhesion to the endothelium is a critical determinant of endothelial injury irrespective of the PMN-activating stimulus.
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PMID:CD18 integrin-dependent endothelial injury: effects of opsonized zymosan and phorbol ester activation. 790 95

Tissue plasminogen activator (t-PA) produced by vascular endothelial cells converts plasminogen to plasmin which degrades fibrin. Since t-PA activity is greatly potentiated in the presence of fibrin (1,2), the activator is implicated in intravascular fibrinolysis. On the other hand, endothelial cells also produce plasminogen activator inhibitor-1 (PAI-1) (3). The inhibitor associated with vascular endothelium rapidly inhibits t-PA, while that released into the liquid phase has a little anti-activator activity (4). However, clinical studies have shown that elevation of plasma PAI-1 level is a risk factor of thrombosis (5,6). It is thus suggested that the balance between t-PA and PAI-1 is important for the regulation of fibrinolysis. The release of t-PA and PAI-1 from vascular endothelial cells is regulated by physiological factors including thrombin (3,7), histamine (8), vasoconstrictor peptide endothelins (9,10) and cytokines (11). In addition, the regulation of the t-PA release and that of the PAI-1 release are not necessarily coupled. It has been shown that activated protein kinase C and cyclic AMP are involved in the stimulation and suppression, respectively, of the endothelial t-PA and PAI-1 production (12,13). However, the role of intracellular calcium in the regulation of endothelial t-PA and PAI-1 release has remained to be elucidated. In the present study, we investigated the effect of calcium ionophore A23187 on the release of t-PA antigen (t-PA:Ag) and PAI-1 antigen (PAI-1:Ag) from cultured vascular endothelial cells derived from human umbilical vein.
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PMID:Calcium regulation of tissue plasminogen activator and plasminogen activator inhibitor-1 release from cultured human vascular endothelial cells. 802 17

Lymphocyte adhesion to vascular endothelium is an important part of immune function. This investigation sought to detect differences between the adhesion of lymphocytes from young and aged human donors to vascular endothelium with and without treatment of the lymphocytes with phorbol myristate acetate (PMA), an activator of protein kinase C (PKC) that stimulates this adhesive process. T-lymphocytes were isolated from young and aged donors and adhesion assays were conducted with human umbilical vein endothelial cells (HUVEC). In some cases the HUVEC were activated by pre-incubation with tumor necrosis factor, a cytokine that increases their adhesiveness, before the addition of lymphocytes in the presence or absence of PMA. The results show that, in the basal state, lymphocytes from young and aged donors had similar levels of adherence, while with PMA activation, lymphocytes from aged donors had a significantly higher level of adherence to both activated and non-activated HUVEC. No cytotoxic effect on the HUVEC was detected. These results suggest a role for lymphocytes in diseases that predominantly affect the elderly and that are thought to involve interaction between lymphocytes and endothelium. In addition, these results indicate that there may be a change in PKC function in lymphocytes with aging.
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PMID:Age-related increase in phorbol myristate acetate-induced lymphocyte adhesion to vascular endothelium. 811 22

Endothelin (ET), a powerful vasoconstrictive peptide, is distributed ubiquitously in various organs, including the vascular endothelium and tubules of the kidney. Although localized more abundantly to the glomerulus and inner medullary collecting duct, ET receptors have been identified in the proximal tubule. The possible effects of ET on proximal tubule transport and the potential role of second messengers in this process have not been described fully. To define the role of ET in proximal tubule transport, renal cortical slices were incubated for 3 min in the presence of various concentrations of ET. Incubation with low concentrations of ET-1 (1 x 10(-9) to 1 x 10(-11) M) within the physiological range stimulated both Na(+)-Pi cotransport and Na+/H+ exchange. Pretreatment with staurosporine (0.6 microM) for 25 min abolished completely the ET-induced effects on Na(+)-Pi cotransport and Na+/H+ exchange. Similarly, preincubation with phorbol ester 12-O-tetradecanoylphorbol-13-acetate (200 nM) also abolished the effects of ET on these transporters. Incubation with ET decreased significantly intracellular adenosine 3',5'-cyclic monophosphate (cAMP). Intravenous administration of pertussis toxin for 2 days prevented the ET-induced decrease in cAMP and abolished the stimulatory effects of ET on Na(+)-Pi cotransport and Na+/H+ exchange. These findings provide indirect evidence that ET participates in the regulation of proximal tubular Pi and bicarbonate homeostasis. These effects of ET are mediated by activation of protein kinase C and cAMP-dependent protein kinase A.
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PMID:Effects of endothelin on rat renal proximal tubule Na(+)-Pi cotransport and Na+/H+ exchange. 818

Fluid shear stress induces a number of morphological and functional changes in vascular endothelium, including a rapid and significant down-regulation of endothelin 1 (ET-1) mRNA and peptide release in bovine aortic endothelial cells. We show here that both the cell alignment and ET-1 down-regulation depend on on-going protein synthesis, and that the latter is the result of a decrease in transcription, as shown by nuclear run-off assay, and not the result of changes in ET-1 mRNA half-life. The treatment of endothelial cells with either phorbol 12-myristate 13-acetate (100 nM) to activate protein kinase C (PKC) or forskolin (10 microM) to stimulate adenylate cyclase sharply decreased ET-1 mRNA. However, the phorbol-induced ET-1 decrease was, unlike the shear-induced down-regulation, independent of active protein synthesis. Physiological shear stress (20 dynes/cm2) did not significantly activate PKC, as assessed by PKC translocation and enzymatic activity assay and failed to increase intracellular cAMP content. Furthermore treatment with calphostin C (1 microM) did not prevent the shear-induced down-regulation of ET-1. DNA transfection experiments suggest that the shear stress-responsive element of the ET-1 gene is contained in the sequence between -2.5 kb and -2.9 kb of the 5'-upstream region. Neither the transcription factor AP-1 binding site nor the GATA-2-factor binding site, necessary for the basal level of transcription of ET-1 gene, is sufficient to confer shear-responsiveness to the reporter gene. These results suggest that shear stress regulates the transcription of the ET-1 gene via an upstream cis element by a distinct mechanism not dependent on the PKC or cAMP pathways.
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PMID:Regulation of endothelin 1 gene by fluid shear stress is transcriptionally mediated and independent of protein kinase C and cAMP. 839 84

We studied whether endothelin (ET)-1 regulates its own transcription in cultured rat aortic endothelial cells (ECs) in an autocrine manner and attempted to elucidate its cellular and molecular mechanism. By Northern blot analysis using rat preproET-1 cDNA as a probe, ET-1 increased steady-state levels of preproET-1 mRNA as early as 30 min, which persisted during 4 h incubation. ET-1 also increased steady-state c-fos mRNA levels, which returned to an undetectable level by 2 h. ET-1 dose-dependently upregulated preproET-1 mRNA expression. The effect was inhibited by nonselective ETA/ETB receptor antagonist but not a selective ETA receptor antagonist. The ET-1-induced preproET-1 mRNA expression was suppressed by a protein kinase C (PKC) inhibitor and by pretreatment with phorbol ester, which depeleted engdogenous PKC. The approximate half-life of preproET-1 mRNA stimulated by ET-1 (approximately 20 min) was similar to that stimulated by phorbol ester. Our data demonstrate that ET-1 upregulates its own gene expression through ETB receptor-mediated PKC activation, suggesting a possible autocrine positive feedback system in vascular endothelium.
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PMID:Autocrine regulation of the endothelin-1 gene in rat endothelial cells. 858 76

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

Studies have shown that, among lipoxygenase metabolites examined, 15(S)-hydroperoxy-5,8,11,13-eicosa-tetraenoic acid (15[S]-HPETE), at micromolar concentrations, selectively causes injury to cultured endothelial cells. We investigated whether physiologically relevant concentrations of lipoxygenase metabolites affected the expression of cell adhesion molecules (CAMs) involved in the adhesion of leukocytes and/or the accumulation of leukocytes in the vascular endothelium, these being the initial events in endothelial cell injury. Among lipoxygenase metabolites, 15(S)-HPETE and 12(S)-HETE, at nanomolar concentrations, induced surface expression of a subset of cell adhesion molecules (CAM), ICAM-1, ELAM-1, and VCAM-1, in human umbilical vein endothelial cells (HUVEC), which is associated with an increased binding activity of the transcription factor, NF-kappa B, to the consensus motif common to the CAM genes in the HUVEC nuclear extracts. Furthermore, 15(S)-HPETE (1 nM) caused a threefold increase in the rate of transendothelial migration of vitamin D3-differentiated HL-60 monocyte-like cells and showed a thirtyfold increase in the phosphorylation of PECAM-1, an adhesion molecule involved in endothelial cell-cell adhesion. Both an antibody to PECAM-1 and the protein kinase C inhibitor, GF 109203X, reduced 15(S)-HPETE-induced transmigration of monocyte-like HL-60 cells by approximately 75% and 85%, respectively. Treatment of HUVEC with a phosphatase inhibitor, calyculin A, augmented both the phosphorylation of PECAM-1 and transmigration of monocyte-like HL-60 cells induced by 15(S)-HPETE. Our results show that 15(S)-HPETE, at physiological concentrations, induced activation of protein kinase C in HUVEC and leads to the phosphorylation of PECAM-1, thus facilitating the migration of monocyte-like HL-60 cells across the endothelial cell monolayer. It is suggested that phosphorylation/dephosphorylation events in PECAM-1 are important in regulating the trafficking of monocytes across the endothelial cell monolayer.
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PMID:Lipoxygenase metabolites induced expression of adhesion molecules and transendothelial migration of monocyte-like HL-60 cells is linked to protein kinase C activation. 865 2

The modern diet is greatly different from that of our paleolithic forebears' in a number of respects. There is reason to believe that many of these dietary shifts can up-regulate intracellular signalling pathways mediated by free intracellular calcium and protein kinase C, particularly in vascular smooth muscle cells; this disorder of intracellular regulation is given the name 'PKC syndrome'. PKC syndrome may entail either a constitutive activation of these pathways, or a sensitization to activation by various agonists. The modern dietary perturbations which tend to induce PKC syndrome may include increased dietary fat and sodium, and decreased intakes of omega-3 fats, potassium, calcium, magnesium and chromium. Insulin resistance may be both a cause and effect of PKC syndrome, and weight reduction and aerobic training should act to combat this disorder. PKC syndrome sensitizes vascular smooth muscle cells to both vasoconstrictors and growth factors, and thus promotes both hypertension and atherogenesis. In platelets, it induces hyperaggregability, while in the microvasculature it may be a mediator of diabetic microangiopathy. In vascular endothelium, intimal macrophages, and hepatocytes, increased protein kinase C activity can be expected to increase cardiovascular risk. Up-regulation of protein kinase C in stem cells may also play a role in the promotion of 'Western' fat-related cancers. Practical guidelines for combatting PKC syndrome are suggested.
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PMID:Up-regulation of intracellular signalling pathways may play a central pathogenic role in hypertension, atherogenesis, insulin resistance, and cancer promotion--the 'PKC syndrome'. 867 54

Excess vascular oxidative stress has been linked to impaired endothelium-dependent arterial relaxation in hypercholesterolemia. alpha-Tocopherol (AT) preserves endothelial function in hypercholesterolemia although the mechanism(s) for this protective effect is (are) not known. We examined the tissue-specific effects of AT on oxidized LDL (ox-LDL)-mediated endothelial dysfunction in male New Zealand White rabbits. Animals consumed chow deficient in (< 10 IU/kg) or supplemented with (1,000 IU/kg) AT for 28 d. Exposure of thoracic aortae from AT-deficient animals to ox-LDL (0-500 microg/ml) for 4 h produced dose-dependent inhibition of acetylcholine-mediated relaxation (P < 0.05) while vessels derived from animals consuming AT were resistant to ox-LDL-mediated endothelial dysfunction. Animals consuming AT demonstrated a 100-fold increase in vascular AT content and this was strongly correlated with vessel resistance to endothelial dysfunction from ox-LDL (R = 0.67; P = 0.0014). These results were not explained by an effect of AT on ox-LDL-mediated cytotoxicity by LDH assay or scanning electron microscopy. Vascular incorporation of AT did produce resistance to endothelial dysfunction from protein kinase C stimulation, an event that has been implicated in the vascular response to ox-LDL. Human aortic endothelial cells loaded with AT also demonstrated resistance to protein kinase C stimulation by both phorbol ester and ox-LDL. Thus, these data indicate that enrichment of vascular tissue with AT protects the vascular endothelium from ox-LDL-mediated dysfunction, at least in part, through the inhibition of protein kinase C stimulation. These findings suggest one potential mechanism for the observed beneficial effect of AT in preventing the clinical expression of coronary artery disease that is distinct from the antioxidant protection of LDL.
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PMID:Vascular incorporation of alpha-tocopherol prevents endothelial dysfunction due to oxidized LDL by inhibiting protein kinase C stimulation. 875 49


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