EC:2.7.11.13 - FACTA Search

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

Breakdown of the blood-retinal barrier (BRB) occurs in several retinal diseases and is a major cause of visual loss. Vascular endothelial growth factor (VEGF) has been implicated as a cause of BRB breakdown in diabetic retinopathy and other ischemic retinopathies, and there is evidence to suggest that other vasopermeability factors may act indirectly through VEGF. In this study, we investigated the effect of several receptor kinase inhibitors on BRB breakdown resulting from VEGF, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), insulin-like growth factor-1 (IGF-1), prostaglandin E1 (PGE(1)), or PGE(2). Inhibitors of VEGF receptor kinase, including PKC412, PTK787, and SU1498, decreased VEGF-induced breakdown of the BRB. None of the inhibitors blocked leakage caused by TNF-alpha, IL-1beta, or IGF-1 and only PKC412, an inhibitor of protein kinase C (PKC) as well as VEGF and platelet-derived growth factor (PDGF) receptor kinases, decreased leakage caused by prostaglandins. Since the other inhibitors of VEGF and/or PDGF receptor kinases that do not also inhibit PKC had no effect on prostaglandin-induced breakdown of the BRB, these data implicate PKC in retinal vascular leakage caused by prostaglandins. PKC412 may be useful for treatment of post-operative and inflammatory macular edema, in which prostaglandins play a role, as well as macular edema associated with ischemic retinopathies.
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PMID:Inhibition of protein kinase C decreases prostaglandin-induced breakdown of the blood-retinal barrier. 1265 48

(1) Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. It has been recently suggested that the inducible heme oxygenase (HO-1) isoform may play a role in angiogenesis. (2) The aims of this study were to determine, in chicken embryo chorioallantoic membranes (CAM), whether VEGF increases HO-1 protein expression, and, if so, by which molecular mechanism, and whether HO-1 activity is required for VEGF-induced angiogenesis. (3) Treatment of CAMs with VEGF for 48 h caused a significant increase in HO-1 protein expression, simultaneously with angiogenesis. (4) VEGF-stimulated angiogenesis in CAMs was markedly attenuated by the HO inhibitor zinc mesoporphyrin (ZnMP). This inhibitory effect of ZnMP was not observed with copper mesoporphyrin (CuMP), a metalloporphyrin that has a similar structure to ZnMP but does not inhibit HO enzymatic activity. (5) Overexpression of HO-1 protein elicited by VEGF in CAMs was significantly attenuated by the intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM). The effects of BAPTA-AM were, in turn, compensated by the calcium ionophore A-23187. (6) In addition, the protein kinase C inhibitor staurosporine significantly attenuated, in a dose-dependent manner, the VEGF-stimulated HO-1 induction observed in CAMs. (7) These results demonstrate, for the first time, that VEGF upregulates HO-1 protein expression in vivo in CAMs by a mechanism dependent on an increase in cytosolic calcium levels and activation of protein kinase C. Our findings also suggest that HO-1 activity is necessary for VEGF-induced angiogenesis in CAMs.
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PMID:Vascular endothelial growth factor increases heme oxygenase-1 protein expression in the chick embryo chorioallantoic membrane. 1278 23

Vascular endothelial growth factor (VEGF) can induce proliferation of endothelial cells through VEGFR-1 and VEGFR-2 as its receptors, but the intracellular signaling pathway via VEGFR-1 is still unclear. Previously we reported that stellate cells expressed VEGFR-1 exclusively during activation in the liver. In the present paper, the signaling pathway via VEGFR-1 was studied using rat stellate cells activated in vitro. Western blot analysis revealed that both ERK/mitogen-activated protein kinase (MAPK) and PI3K/Akt were phosphorylated in the cells activated by culture in Dulbecco's modified Eagle medium containing 10% fetal calf serum on plastic dishes for 9 days. When VEGF was added to the culture medium, the extent of such PI3K/Akt phosphorylation was increased despite that DNA synthesis and ERK/MAPK phosphorylation were unchanged in the cells. However, this up-regulation of PI3K/Akt phosphorylation was markedly diminished following addition of GFX and PD-98059, inhibitors for protein kinase C (PKC) and ERK/MAPK, respectively. Also, addition of GFX reduced phosphorylation of ERK/MAPK in the cells. It is suggested that VEGF may stimulate signal transduction of PI3K/Akt through VEGFR-1 dependently on activation of the PKC and ERK/MAPK pathway in activated hepatic stellate cells.
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PMID:ERK/MAPK-dependent PI3K/Akt phosphorylation through VEGFR-1 after VEGF stimulation in activated hepatic stellate cells. 1285 Jun 96

Vascular endothelial growth factor (VEGF) is known as a key regulator of angiogenesis during endochondral bone formation. Recently, we demonstrated that TNF-related activation-induced cytokine (TRANCE or RANKL), which is essential for bone remodeling, also had an angiogenic activity. Here we report that VEGF up-regulates expression of receptor activator of NF-kappa B (RANK) and increases angiogenic responses of endothelial cells to TRANCE. Treatment of human umbilical vein endothelial cells (HUVECs) with VEGF increased both RANK mRNA and surface protein expression. Although placenta growth factor specific to VEGF receptor-1 had no significant effect on RANK expression, inhibition of downstream signaling molecules of the VEGF receptor-2 (Flk-1/KDR) such as Src, phospholipase C, protein kinase C, and phosphatidylinositol 3'-kinase suppressed VEGF-stimulated RANK expression in HUVECs. Moreover, the MEK inhibitor PD98059 or expression of dominant negative MEK1 inhibited induction of RANK by VEGF but not the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM). VEGF potentiated TRANCE-induced ERK activation and tube formation via RANK up-regulation in HUVECs. Together, these results show that VEGF enhances RANK expression in endothelial cells through Flk-1/KDR-protein kinase C-ERK signaling pathway, suggesting that VEGF plays an important role in modulating the angiogenic action of TRANCE under physiological or pathological conditions.
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PMID:Vascular endothelial growth factor up-regulates expression of receptor activator of NF-kappa B (RANK) in endothelial cells. Concomitant increase of angiogenic responses to RANK ligand. 1289 32

Vascular endothelial growth factor receptor-2 (VEGFR-2/KDR/Flk-1) is a high-affinity receptor for vascular endothelial growth factor-A (VEGF-A), and mediates most of the endothelial growth and survival signals from VEGF-A. VEGFR-2 has a typical tyrosine kinase receptor structure with seven immunoglobulin (Ig)-like domains in the extracellular region, as well as a long kinase insert in the tyrosine kinase domain. It utilizes a unique signaling system for DNA synthesis in vascular endothelial cells, i.e. a phospholipase C gamma-protein kinase C-Raf-MAP kinase pathway. Although VEGF-A binds two receptors, VEGFR-1 and -2, a newly isolated ligand VEGF-E (Orf-virus-derived VEGF) binds and activates only VEGFR-2. Transgenic mice expressing VEGF-E(NZ-7) showed a dramatic increase in angiogenesis with very few side effects (such as edema and hemorrhagic spots), suggesting strong angiogenic signaling and a potential clinical utility of VEGF-E. VEGF family members bear three loops produced via three intramolecular disulfide bonds, and cooperation between loop-1 and loop-3 is necessary for the specific binding and activation of VEGFR-2 for angiogenesis. As it directly upregulates tumor angiogenesis, VEGFR-2 is an appropriate target for suppression of solid tumor growth using exogenous antibodies, small inhibitory molecules and in vivo stimulation of the immune system.
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PMID:Vascular endothelial growth factor receptor-2: its unique signaling and specific ligand, VEGF-E. 1296 71

Vascular endothelial growth factor (VEGF) increases vascular permeability by stimulating endothelial Ca(2+) influx. Here we provide evidence that links VEGF-mediated increased permeability and endothelial intracellular Ca(2+) concentration ([Ca(2+)](i)) with diacylglycerol (DAG)-mediated activation of the transient receptor potential channels (TRPCs). We used the Landis-Michel technique to measure changes in hydraulic conductivity (L(p)) and fluorescence photometry to quantify changes in endothelial [Ca(2+)](i) in individually perfused Rana mesenteric microvessels in vivo and transfected nonendothelial cells in vitro. The membrane-permeant DAG analog 1-oleoyl-2-acetyl-sn-glycerol (OAG, 100 microM), which is known to increase Ca(2+) influx through TRPCs, transiently increased L(p) 3.8 +/- 1.2-fold (from 1.6 +/- 0.8 to 9.8 +/- 2.7 x 10(-7) cm.s(-1).cmH(2)O(-1); P < 0.0001; n = 18). Protein kinase C inhibition by bisindolylmaleimide (1 microM) did not affect the OAG-induced increases in L(p). OAG also significantly increased microvascular endothelial [Ca(2+)](i) in vivo (n = 13; P < 0.0001), which again was not sensitive to protein kinase C inhibition. VEGF induced a transient increase in endothelial [Ca(2+)](i) in human embryonic kidney cells (HEK-293) that were cotransfected with VEGF receptor 2 and TRPC-6 but not with control, VEGF receptor 2, or TRPC-6 expression vector alone (P < 0.01; n = 9). Flufenamic acid, which has been shown to enhance activity of TRPC-6 but inhibit TRPC-3 and -7, enhanced the VEGF-mediated increase in L(p) in approximately half of the vessels tested but inhibited the response in the other half of the vessels. These data provide evidence consistent with the hypothesis that VEGF increases vascular permeability via DAG-mediated Ca(2+) entry through TRPCs. Although the exact identities of the TRPCs remain to be confirmed, TRPC-6 appears to be a likely candidate in approximately half of the vessels.
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PMID:Evidence of a role for TRPC channels in VEGF-mediated increased vascular permeability in vivo. 1455 Oct 41

Vascular endothelial growth factor (VEGF) is a major agent in choroidal and retinal neovascularization, events associated with age-related macular degeneration (AMD) and diabetic retinopathy. Retinal pigment epithelium (RPE), strategically located between retina and choroid, plays a critical role in retinal disorders. We have examined the effects of various growth factors on the expression and secretion of VEGF by human retinal pigment epithelial cell cultures (HRPE). RT-PCR analyses revealed the presence of three isoforms of mRNA corresponding to VEGF 121, 165, and 189 that were up regulated by TGF-beta1. TGF-beta1, beta2, and beta3 were the potent inducers of VEGF secretion by HRPE cells whereas bFGF, PDGF, TGF-alpha, and GM-CSF had no effects. TGF-beta receptor type II antibody significantly reversed induction of VEGF secretion by TGF-beta. In contrast activin, inhibin and BMP, members of TGF-beta super family, had no effects on VEGF expression in HRPE. VEGF mRNA levels and protein secretion induced by TGF-beta were significantly inhibited by SB203580 and U0126, inhibitors of MAP kinases, but not by staurosporine and PDTC, protein kinase C and NF-kappaB pathway inhibitors, respectively. TGF-beta also induced VEGF expression by fibroblasts derived from human choroid of eye. TGF-beta induction of VEGF secretion by RPE and choroid cells may play a significant role in choroidal neovascularization (CNV) in AMD. Since the secretion of VEGF by HRPE is regulated by MAP kinase pathways, MAP kinase inhibitors may have potential use as therapeutic agents for CNV in AMD.
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PMID:Transforming growth factor-beta induces expression of vascular endothelial growth factor in human retinal pigment epithelial cells: involvement of mitogen-activated protein kinases. 1456 75

Vascular endothelial growth factor (VEGF) is highly expressed in the airway of patients with asthma. Whether VEGF affects eosinophil function in vitro and if VEGF receptors are involved was tested. Eosinophils were from venous blood of healthy donors. Cell migration was studied by micropore filter assays. Signaling mechanisms required for VEGF-dependent migration were tested using signaling enzyme blockers. Expression of flt-1 and KDR/flk-1 mRNA in eosinophils was demonstrated in reverse transcriptase-polymerase chain reaction, and receptor expression was investigated by fluorescence-activated cell sorting analysis. Eosinophil cationic protein release was measured in eosinophil supernatants by enzyme-linked immunosorbent assay. VEGF significantly stimulated eosinophil chemotaxis via activation of protein kinase C and phosphatidylinositol 3'-kinase. The effect on migration was reversed by an antibody against VEGF receptor flt-1, but not by an antibody against KDR/flk-1. Expression of VEGF receptor flt-1 mRNA was shown and synthesis of VEGF receptor in eosinophils is suggested by detection of VEGF receptor immunoreactivity on the cell surface. Data suggest that VEGF receptor flt-1 is expressed by eosinophils whose activation with VEGF stimulates directed migration and release of eosinophil cationic protein. Thus, VEGF may play an important role in the modulation of eosinophilic inflammation.
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PMID:Expression and function of the vascular endothelial growth factor receptor FLT-1 in human eosinophils. 1460 15

Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen that promotes angiogenesis, vasculogenesis, and increases vascular permeability. VEGF is expressed in renal tubular epithelial cells and urinary VEGF excretion is increased in various glomerular disorders. However, the mechanisms underlying expression of VEGF in renal tubular epithelial cells have not been fully elucidated. In the present study, we attempted to define a predominant regulator of VEGF expression using a cultured murine renal proximal tubular epithelial cell line (mProx24). VEGF protein concentration in the culture supernatant was measured by sandwich enzyme-linked immunosorbent assay. mProx24 constitutively produced VEGF at low level. Major isoforms expressed in this cell line were VEGF164 and VEGF120 determined by reverse transcription-polymerase chain reaction method. Among various stimuli including angiotensin II, transforming growth factor-beta1 (TGF-beta1), lipopolysaccharides, interleukin-1beta, interleukin-10 and interferon-gamma, only TGF-beta1 significantly increased the level of VEGF protein at 24 h in a dose-dependent manner. The steady-state mRNA level of VEGF was dose dependently increased by TGF-beta1 detected by Northern blotting. Treatment with neutralizing anti-TGF-beta1 antibody abolished TGF-beta1-induced VEGF expression by 70%. Inhibitors of protein kinase C (PKC), Ro-31-8220 and staurosporin, significantly suppressed TGF-beta1-induced VEGF protein expression. These results demonstrate the role of TGF-beta1 on the expression of VEGF in proximal tubular epithelial cells mediated potentially via PKC pathway. This regulatory mechanism may be associated with the progression of tubulointerstitial lesions in renal disorders.
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PMID:Transforming growth factor-beta 1 induces vascular endothelial growth factor expression in murine proximal tubular epithelial cells. 1461 Mar 27

Reactive oxygen species (ROS) mediate cell damage and have been implicated in the pathogenesis of diseases that involve endothelial injury. Cells possess antioxidant systems, including intracellular antioxidants and ROS scavenging enzymes, that control the redox state and prevent cell damage. In addition to intracellular antioxidants, certain growth factor receptors can be activated under oxidative stress and trigger downstream cell survival signaling cascades. Vascular endothelial growth factor receptor-3 (VEGFR-3) is a primary modulator of lymphatic endothelial proliferation and survival. Here, we provide evidence that activation of VEGFR-3 signaling in response to hydrogen peroxide (H(2)O(2)) promotes endothelial cell survival. Treatment with H(2)O(2) induced the tyrosine phosphorylation of VEGFR-3 and its association with the signaling adaptor proteins Shc, growth factor receptor binding protein 2, Sos, p85, SHP-2, and phospholipase C-gamma. Of note, a hereditary lymphoedema-linked mutant of VEGFR-3 was not phosphorylated by H(2)O(2) treatment. Isoforms of protein kinase C (PKC), alpha and delta, were also tyrosine-phosphorylated after H(2)O(2) stimulation. However, only the delta isoform of PKC was required for H(2)O(2)-induced phosphorylation of VEGFR-3. The tyrosine phosphorylation of VEGFR-3 or isoforms of PKC was completely inhibited by treatment with 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, a specific inhibitor for Src family kinases, indicating that Src family kinases are upstream of PKC and VEGFR-3. Furthermore, expression of the wild-type but not the lymphoedema-linked mutant form of VEGFR-3 in porcine artery endothelial cells significantly enhanced the activation of Akt after H(2)O(2) stimulation. Consistent with these biochemical changes, we observed that expression and activation of the wild-type but not the mutant form of VEGFR-3 inhibited H(2)O(2)-induced apoptosis. These studies suggest that VEGFR-3 protects against oxidative damage in endothelial cells, and that patients with hereditary lymphoedema may be susceptible to ROS-induced cell damage.
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PMID:Activation of vascular endothelial growth factor receptor-3 and its downstream signaling promote cell survival under oxidative stress. 1510 29

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