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)

Reactive oxygen species play an important role in development of lung injury. Neonates exhibit a high risk of developing acute and/or chronic lung disorder, often associated with surfactant deficiency, and in parallel they show low vitamin E concentration. We investigated whether the vitamin E status of adult rats affects the content of phospholipids (PL) in bronchoalveolar lavage and alveolar type II cells. Phosphatidylcholine (PtdCho) is the dominant and functional most important PL in lung surfactant. Therefore, we determined its formation via de novo synthesis and reacylation of lyso-PtdCho in type II cells. Vitamin E depletion caused a decrease of PL content in bronchoalveolar lavage and type II cells and decreased glycerol-3-phosphate O-acyltransferase (G3P-AT) activity, de novo synthesis of PtdCho, and reacylation of lyso-PtdCho in type II cells. Preincubation of type II cell homogenates with dithiothreitol restored the activity of G3P-AT and de novo synthesis but inhibited reacylation. Reacylation was strongly reduced by chelerythrine-mediated inhibition of protein kinase C. We conclude that antioxidant and PKC-modulating properties of vitamin E regulate de novo synthesis of PtdCho and reacylation of lyso-PtdCho in alveolar type II cells. Vitamin E depletion reduced the two pathways of PL synthesis and caused a decrease of PL content in alveolar surfactant of rats.
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PMID:Vitamin E deficiency reduces surfactant lipid biosynthesis in alveolar type II cells. 1263 43

Vitamin E, the most important lipid-soluble antioxidant, was discovered at the University of California at Berkeley in 1922. Since its discovery, studies of the constituent tocopherols and tocotrienols have focused mainly on their antioxidant properties. In 1991 Angelo Azzi's group (Boscoboinik et al. 1991a,b) first described non-antioxidant cell signalling functions for alpha-tocopherol, demonstrating that vitamin E regulates protein kinase C activity in smooth muscle cells. At the transcriptional level, alpha-tocopherol modulates the expression of the hepatic alpha-tocopherol transfer protein, as well as the expression of liver collagen alphal gene, collagenase gene and alpha-tropomyosin gene. Recently, a tocopherol-dependent transcription factor (tocopherol-associated protein) has been discovered. In cultured cells it has been demonstrated that vitamin E inhibits inflammation, cell adhesion, platelet aggregation and smooth muscle cell proliferation. Recent advances in molecular biology and genomic techniques have led to the discovery of novel vitamin E-sensitive genes and signal transduction pathways.
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PMID:Regulation of cell signalling by vitamin E. 1269 Nov 70

Glomerular endothelial cells(GEC) produce monocyte chemoattractant protein-1(MCP-1), which is considered to be an important factor for the recruitment of macrophages into the glomeruli. Recent reports have suggested an association between oxidized low-density lipoprotein(ox-LDL) and progression of glomerular disease. In this study, the effects of lysophosphatidylcholine(LysoPC), a modified phospholipid produced during LDL oxidation, on MCP-1 mRNA expression in cultured bovine GEC were examined. GEC from the 8th through 10th passages were used. LysoPC substantially increased expression of MCP-1 mRNA when compared to the control. These findings led us to examine the mechanism of LysoPC-induced MCP-1 expression in GEC. LysoPC-induced MCP-1 mRNA expression in GEC was suppressed by genistein and staurosporine. It was suggested that both the tyrosinekinase(TK) and proteinkinase C(PKC) pathways were involved in LysoPC-induced MCP-1 expression in GEC. MCP-1 mRNA induction by LysoPC was also attenuated by Vitamin E. This effect may be related to the beneficial effects of Vitamin E on experimental glomerular disease models. In conclusion, LysoPC increased MCP-1 expression in GEC. This phenomenon is believed to be mediated by both the TK and PKC signaling pathways, in contrast with other vascular endothelial cells. Vitamin E also attenuated LysoPC-induced MCP-1 expression in GEC.
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PMID:[Effects of lysophosphatidylcholine on expression of monocyte chemoattractant protein-1 in glomerular endothelial cells]. 1270 2

1. Phospholipid metabolites lysophospholipids cause extracellular K(+) accumulation and action potential shortening with increased risk of arrhythmias during myocardial ischemia. Here we studied effects of several lysophospholipids with different lengths of hydrocarbon chains and charged headgroups on HERG K(+) currents (I(HERG)) expressed in HEK293 cells and the potential mechanisms using whole-cell patch-clamp techniques. 2. Only the lipids with 16 hydrocarbons such as 1-palmitoyl-lysophosphatidylcholine (LPC-16) and 1-palmitoyl-lysophosphatidylglycerol (LPG-16) were found to produce significant enhancement of I(HERG) and negative shifts of HERG activation, although the voltage dependence of the effects was different between LPC-16 and LPG-16 which have differently charged headgroups. The lipid with 18 hydrocarbons modestly increased I(HERG). The lipids with 6 or 24 hydrocarbons had no effect or slightly decreased I(HERG). 3. Inhibition or activation of protein kinase C did not alter the effects of LPC-16 and LPG-16. Participation of phosphatidylinositol-4,5-bisphosphate in I(HERG) enhancement by LPC-16/LPG-16 was also excluded. 4. Vitamin E augmented the effects of LPC-16/LPG-16 whereas xanthine/xanthine oxidase reduced I(HERG): indicating that LPC-16/LPG-16 produced dual effects on I(HERG): direct enhancement of I(HERG) and indirect suppression via production of superoxide anion. 5. We conclude that enhancement of HERG function by lysophospholipids is specific to the lipids with 16-hydrocarbon chain structure and the pattern of voltage dependence is determined by the polar headgroups. The increase in I(HERG) is best described by direct interactions between lipid molecules and HERG proteins, which is consistent with lack of effects via membrane destabilization or modulation by intracellular signaling pathways.
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PMID:Potential mechanisms for the enhancement of HERG K+ channel function by phospholipid metabolites. 1474 14

The development of atherosclerosis is a multifactorial process in which both elevated plasma cholesterol levels and proliferation of smooth muscle cells play a central role. Numerous studies have suggested the involvement of oxidative processes in the pathogenesis of atherosclerosis and especially of oxidized low density lipoprotein. Some epidemiological studies have shown an association between high dietary intake and high serum concentrations of vitamin E and lower rates of ischemic heart disease. Cell culture studies have shown that alpha-tocopherol brings about inhibition of smooth muscle cell proliferation. This takes place via inhibition of protein kinase C activity. alpha-Tocopherol also inhibits low density lipoprotein induced smooth muscle cell proliferation and protein kinase C activity. The following animal studies showed that vitamin E protects development of cholesterol induced atherosclerosis by inhibiting protein kinase C activity in smooth muscle cells in vivo. Elevated plasma levels of homocysteine have been identified as an important and independent risk factor for cerebral, coronary and peripheral atherosclerosis. However the mechanisms by which homocysteine promotes atherosclerotic plaque formation are not clearly defined. Earlier reports have been suggested that homocysteine exert its effect via H2O2 produced during its metabolism. To evaluate the contribution of homocysteine in the pathogenesis of vascular diseases, we examined whether the homocysteine effect on vascular smooth muscle cell growth is mediated by H2O2. We show that homocysteine induces DNA synthesis and proliferation of vascular smooth muscle cells in the presence of peroxide scavenging enzyme, catalase. Our data suggest that homocysteine induces smooth muscle cell growth through the activation of an H2O2 independent pathway and accelerate the progression of atherosclerosis. The results indicate a cellular mechanism for the atherogenicity of cholesterol or homocysteine and protective role of vitamin E in the development of atherosclerosis.
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PMID:Molecular mechanisms of cholesterol or homocysteine effect in the development of atherosclerosis: Role of vitamin E. 1475 78

Atherosclerosis and its complications such as coronary heart disease, myocardial infarction and stroke are the leading causes of death in the developed world. High blood pressure, diabetes, smoking and a diet high in cholesterol and lipids clearly increase the likelihood of premature atherosclerosis, albeit other factors, such as the individual genetic makeup, may play an additional role. Several epidemiological studies and intervention trials have been performed with vitamin E, and some of them showed that it prevents atherosclerosis. For a long time, vitamin E was assumed to act by decreasing the oxidation of LDL, a key step in atherosclerosis initiation. However, at the cellular level, vitamin E acts by inhibition of smooth muscle cell proliferation, platelet aggregation, monocyte adhesion, oxLDL uptake and cytokine production, all reactions implied in the progression of atherosclerosis. Recent research revealed that these effects are not the result of the antioxidant activity of vitamin E, but rather of precise molecular actions of this compound. It is assumed that specific interactions of vitamin E with enzymes and proteins are at the basis of its non-antioxidant effects. Vitamin E influences the activity of several enzymes (e.g. PKC, PP2A, COX-2, 5-lipooxygenase, nitric oxide synthase, NADPH-oxidase, superoxide dismutase, phopholipase A2) and modulates the expression of genes that are involved in atherosclerosis (e.g. scavenger receptors, integrins, selectins, cytokines, cyclins). These interactions promise to reveal the biological properties of vitamin E and allow designing better strategies for the protection against atherosclerosis progression.
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PMID:Anti-atherosclerotic effects of vitamin E--myth or reality? 1509 Feb 61

Molecules in biological systems often can perform more than one function. In particular, many molecules have the ability to chemically scavenge free radicals and thus act in the test tube as antioxidant, but their main biological function is by acting as hormones, ligands for transcription factors, modulators of enzymatic activities or as structural components. In fact, oxidation of these molecules may impair their biological function, and cellular defense systems exist which protect these molecules from oxidation. Vitamin E is present in plants in 8 different forms with more or less equal antioxidant potential (alpha-, beta-, gamma-, delta-tocopherol/tocotrienols); nevertheless, in higher organisms only alpha-tocopherol is preferentially retained suggesting a specific mechanism for the uptake for this analogue. In the last 20 years, the route of tocopherol from the diet into the body has been clarified and the proteins involved in the uptake and selective retention of alpha-tocopherol discovered. Precise cellular functions of alpha-tocopherol that are independent of its antioxidant/radical scavenging ability have been characterized in recent years. At the posttranslational level, alpha-tocopherol inhibits protein kinase C, 5-lipoxygenase and phospholipase A2 and activates protein phosphatase 2A and diacylglycerol kinase. Some genes (e. g. scavenger receptors, alpha-TTP, alpha-tropomyosin, matrix metalloproteinase-19 and collagenase) are modulated by alpha-tocopherol at the transcriptional level. alpha-Tocopherol also inhibits cell proliferation, platelet aggregation and monocyte adhesion. These effects are unrelated to the antioxidant activity of vitamin E, and possibly reflect specific interactions of alpha-tocopherol with enzymes, structural proteins, lipids and transcription factors. Recently, several novel tocopherol binding proteins have been cloned, that may mediate the non-antioxidant signaling and cellular functions of vitamin E and its correct intracellular distribution. In the present review, it is suggested that the non-antioxidant activities of tocopherols represent the main biological reason for the selective retention of alpha-tocopherol in the body, or vice versa, for the metabolic conversion and consequent elimination of the other tocopherols.
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PMID:Non-antioxidant activities of vitamin E. 1513 10

The class B scavenger receptor, CD36, binds to oxidized LDL (OxLDL), is present in atherosclerotic lesions, and is upregulated by OxLDL or AcLDL. Previously we have shown that RRR-alpha-tocopherol (AT) enrichment of human monocyte-derived macrophages inhibited OxLDL or AcLDL induced CD36 expression. The mechanism by which AT inhibited CD36 expression is not known. In the present study, we explored the mechanism by which AT decreases CD36 expression in human macrophages. Macrophages were enriched with AT (100 microM) or N-acetyl cysteine (NAC, 6 mM) overnight and then incubated with oxLDL or AcLDL for 48 h. The effect of protein kinase C inhibitors, and tyrosine kinase inhibitors on OxLDL or AcLDL-induced CD36 expression was quantitated by flow cytometry. Protein kinase C inhibitors or NAC had no effect while there was a significant inhibition with tyrosine kinase inhibitors (P < 0.01). OxLDL or AcLDL significantly increased tyrosine kinase activity which was significantly inhibited by pre-incubation with AT or with tyrosine kinase inhibitors. Western blotting revealed an increase in Tyk2 as well as phosphotyk2 with OxLDL or AcLDL. Immunoprecipitation of CD36 followed by Western blotting with Tyk2 antibodies revealed that Tyk2 was associated with CD36. In conclusion, this study demonstrates an additional direct cellular effect of AT, i.e. inhibition of CD36 expression via inhibition of tyrosine kinase (Tyk2).
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PMID:RRR-alpha-tocopherol decreases the expression of the major scavenger receptor, CD36, in human macrophages via inhibition of tyrosine kinase (Tyk2). 1526 76

alpha-Tocopherol modulates two major signal transduction pathways centered on protein kinase C and phosphatidylinositol 3-kinase. Changes in the activity of these key kinases are associated with changes in cell proliferation, platelet aggregation, and NADPH-oxidase activation. Several genes are also regulated by tocopherols partly because of the effects of tocopherol on these two kinases, but also independently of them. These genes can be divided in five groups: Group 1. Genes that are involved in the uptake and degradation of tocopherols: alpha-tocopherol transfer protein, cytochrome P450 (CYP3A), gamma-glutamyl-cysteine synthetase heavy subunit, and glutathione-S-transferase. Group 2. Genes that are implicated with lipid uptake and atherosclerosis: CD36, SR-BI, and SR-AI/II. Group 3. Genes that are involved in the modulation of extracellular proteins: tropomyosin, collagen-alpha-1, MMP-1, MMP-19, and connective tissue growth factor. Group 4. Genes that are connected to adhesion and inflammation: E-selectin, ICAM-1 integrins, glycoprotein IIb, IL-2, IL-4, IL-1b, and transforming growth factor-beta (TGF-beta). Group 5. Genes implicated in cell signaling and cell cycle regulation: PPAR-gamma, cyclin D1, cyclin E, Bcl2-L1, p27, CD95 (APO-1/Fas ligand), and 5a-steroid reductase type 1. The transcription of p27, Bcl2, alpha-tocopherol transfer protein, cytochrome P450 (CYP3A), gamma-glutamyl-cysteine sythetase heavy subunit, tropomyosin, IL-2, and CTGF appears to be upregulated by one or more tocopherols. All the other listed genes are downregulated. Gene regulation by tocopherols has been associated with protein kinase C because of its deactivation by alpha-tocopherol and its contribution in the regulation of a number of transcription factors (NF-kappaB, AP1). A direct participation of the pregnane X receptor (PXR) / retinoid X receptor (RXR) has been also shown. The antioxidant-responsive element (ARE) and the TGF-beta-responsive element (TGF-beta-RE) appear in some cases to be implicated as well.
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PMID:Vitamin E mediates cell signaling and regulation of gene expression. 1575 36

The intracellular bacterium Chlamydia pneumoniae is involved in the inflammation process of atherosclerosis. We previously demonstrated that C. pneumonia infected monocytes (THP-1 cells) responded to stimulation by an increased respiratory burst linked to an increased NADPH oxidase (NOX) activity. We now tested agents acting on the assembly of the NOX subunits or on protein kinase C, a trigger of NOX activity. Apocynin, resveratrol, rutin, quercetin, curcumin, and tocopherols were tested. The cells were pre-incubated with Chlamydia and the agent for 19 h, and then stimulated with phorbol myristate acetate. The NOX activity was monitored by measuring the hydrogen peroxide production. Resveratrol and curcumin (10(-4)-10(-6) M) were better inhibitors than apocynin. alpha-Tocopherol was inactive, and gamma-tocopherol inhibitor at 10(-4) M only. Quercetin was inactive, and rutin a moderate but significant inhibitor. The inhibition by resveratrol was increased by 10(-6) M rutin or quercetin. Resveratrol and curcumin thus appeared to be interesting for atherosclerosis treatment.
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PMID:Resveratrol and curcumin reduce the respiratory burst of Chlamydia-primed THP-1 cells. 1593 98


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