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)

Hyperglycemia causes vascular complications of diabetes possible by the activation of protein kinase C (PKC). We have provided substantial evidence that activation of PKC can lead to a whole host of vascular dysfunction in diabetes. The activation of PKC induced by hyperglycemia appears to be due to an increase in diacylglycerol (DAG) levels, a physiological activator of PKC. Studies involving cultural cells, animal models of diabetes and patients have shown that inhibition of PKC by specific PKC inhibitor was able to reverse many of the vascular dysfunctions in the retina, kidney and cardiovascular systems induced by either hyperglycemia or diabetes. In addition high doses of vitamin E were shown to decrease the level of DAG and PKC induced by diabetes or hyperglycemia. Thus animal and clinical studies have shown that high doses of vitamin E treatment can apparently reverse some of the changes in the retinal and renal vessels.
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PMID:Can protein kinase C inhibition and vitamin E prevent the development of diabetic vascular complications? 1058 70

We have reported that d-alpha-tocopherol can prevent hyperglycemia-induced activation of DAG and PKC levels in vascular tissues as well as normalizing retinal blood flow and renal hyperfiltration. The mechanism of this effect, however, is not clear. Aside from alpha-tocopherol's principal role as an antioxidant agent, it has also been shown to act as a membrane stabilizer. Another possibility is that the effect of alpha-tocopherol is focused on the activation of DAG kinase, which is a key enzyme in the metabolism of DAG. Therefore, in this study, we examined the effect of alpha-tocopherol on the DAG kinase activity in vascular smooth muscle cell. We have also examined the effect of alpha-tocopherol, its analogues, and probucol on DAG kinase activities and expression. The present study showed that d-alpha-tocopherol's inhibitory effect on DAG-PKC pathway is by increasing DAG kinase activity in rat and human vascular smooth muscle cell (VSMC). Total DAG level was increased by 40 +/- 10% (mean +/- S.E.) (P < 0.05) in human VSMC, after exposure to 22 vs 5 mM glucose. This increase was normalized by d-alpha-tocopherol treatment in a concentration-dependent manner. In parallel, DAG kinase activation by d-alpha-tocopherol was also induced in a time- and dose-dependent manner. DAG kinase activity was increased by 57 +/- 19% (P < 0.05) in human VSMC and 112 +/- 35% (P < 0.05) in rat VSMC after 24 h of incubation with d-alpha-tocopherol (100 microg/ml). Another lipophilic antioxidant, probucol, also increased DAG kinase activity by 124 +/- 34%, but other vitamin E analogues with much less antioxidant potencies were ineffective. Western blots of various DAG kinase isoforms were not changed by d-alpha-tocopherol treatment. These results provide strong and detailed evidence that d-alpha-tocopherol can prevent hyperglycemia induced DAG-PKC activation by enhancing DAG kinase activity, probably through an antioxidant effect.
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PMID:d-Alpha-tocopherol prevents the hyperglycemia induced activation of diacylglycerol (DAG)-protein kinase C (PKC) pathway in vascular smooth muscle cell by an increase of DAG kinase activity. 1058 71

Although superoxide can directly quench endothelium-generated nitric oxide (NO), there is considerable evidence that oxidants derived from superoxide--notably peroxides and their further derivatives--can also impair NO bioactivity. In part, this reflects inhibition of NO synthase activity, perhaps mediated by the oxidation of labile sulfhydryl groups, as well as the activation of protein kinase C. Selenium deficiency exacerbates these effects, presumably owing to the crucial role of selenium-dependent thioredoxin reductase and glutathione peroxidases in preventing and reversing oxidant damage to proteins. High-normal homocyst(e)ine levels may induce an 'effective selenium deficiency' by suppressing glutathione peroxidase transcription in endothelial cells. Considerable epidemiology, primarily of European origin, points to mediocre selenium nutrition as a significant vascular risk factor; the risk associated with elevated plasma homocyst(e)ine levels is now well established. In addition to preventing LDL oxidation, vitamin E can be expected to minimize the contribution of lipid peroxides to endothelial dysfunction. Lipoic acid, which can function in vivo as a versatile antioxidant and sulfhydryl reductant, may have particular value for protecting endothelium from oxidants; its clinical utility in diabetic neuropathy may reflect this benefit. Good selenium status, as well as supra-nutritional intakes of lipoic acid, may down-regulate cytokine-mediated endothelial activation by helping to maintain the proper structure of oxidant-labile proteins--such as tyrosine phosphatases--that modulate this signaling. It can be concluded that a number of supplemental nutrients--including selenium, vitamin E, lipoic acid, and the vitamins that promote catabolism of homocysteine--have the potential to promote vascular health by mitigating the adverse impact of superoxide-derived oxidants on endothelial function.
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PMID:Oxidants downstream from superoxide inhibit nitric oxide production by vascular endothelium--a key role for selenium-dependent enzymes in vascular health. 1060 66

The effects of vitamin A and vitamin E treatment on superoxide (O2-) production of neutrophils and their intracellular signaling, including intracellular Ca2+, protein kinase C (PKC), and tyrosine kinase (TK), were examined in Holstein calves. After treatment with vitamin A, heat-aggregated IgG (H-agg.IgG)-induced O2- production in neutrophils ranged from 3.7+/-0.4 to 4.3+/-0.9 nmol (mean +/- SD), and it was significantly (P<0.05) higher than that in the control calves. Opsonized zymosan (OPZ)-induced O2- production was similar with that of control calves. Intracellular signaling of neutrophils in vitamin A-treated calves was enhanced compared with that of control calves when stimulated with H-agg. IgG, but not with OPZ. After treatment with vitamin E, H-agg.IgG- and OPZ-induced O2- production of neutrophils ranged from 4.2+/-0.8 nmol to 5.4+/-0.5 nmol and from 7.8+/-0.6 nmol to 8.1+/-0.4 nmol (mean +/- SD), respectively, and they were significantly (P<0.05) higher than those in control calves. Intracellular signaling was also enhanced compared with that of control calves. These results suggested that the effects of vitamin A and E treatment on O2- production were correlated to changes in intracellular signaling of neutrophils in Holstein calves.
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PMID:Effects of vitamins A and E on superoxide production and intracellular signaling of neutrophils in Holstein calves. 1068 Jun 60

Vitamin E was originally considered a dietary factor of animal nutrition especially important for normal reproduction. The significance of vitamin E has been subsequently proven as a radical chain breaking antioxidant that can protect the integrity of tissues and play an important role in life processes. More recently alpha-tocopherol has been found to possess functions that are independent of its antioxidant/radical scavenging ability. Absorption in the body is alpha-tocopherol selective and other tocopherols are not absorbed or are absorbed to a lesser extent. Furthermore, pro-oxidant effects have been attributed to tocopherols as well as an anti-nitrating action. Non-antioxidant and non-pro-oxidant molecular mechanisms of tocopherols have been also described that are produced by alpha-tocopherol and not by beta-tocopherol. alpha-Tocopherol specific inhibitory effects have been seen on protein kinase C, on the growth of certain cells and on the transcription of some genes (CD36, and collagenase). Activation events have been seen on the protein phosphatase PP2A and on the expression of other genes (alpha-tropomyosin and Connective Tissue Growth Factor). Non-antioxidant molecular mechanisms have been also described for gamma-tocopherol, delta-tocopherol and tocotrienols.
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PMID:Vitamin E: non-antioxidant roles. 1079 17

The effects of exogenous oxidative stress due to passive smoking on cholesteryl ester (CE)-metabolizing enzymes and their regulatory kinases were examined by exposing rats to cigarette smoke (CS) for a 1-h period twice a day for 8, 12, or 20 wk. An oxidatively modified low density lipoprotein (Ox-LDL) with a high lipid peroxide was identified in three CS groups after all three exposure periods. The rat aortic acid and neutral CE hydrolases (ACEH and NCEH) were activated to similar extents by both cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) in the presence of their respective cofactors. The aortic PKC activity in the three CS groups exhibited significant reductions of 72, 84, and 75% as compared with the respective controls, which coincided with the reductions in the ACEH activities (86, 71, and 80%, respectively), whereas the PKA activities increased to 121, 197, and 252% in the three CS groups, respectively. Reflecting the increase of the PKA activity, the NCEH activity exhibited increases of 112% at 8 wk and 140% until 12 wk of exposure and decreased by 50% of the control value at 20 wk of exposure, suggesting inactivation of NCEH itself. The activation of acyl-CoA:cholesterol O-acyltransferase activity was associated with an increase of free cholesterol in aorta. The vitamin E diet prevented the formation of Ox-LDL and the oxidative inactivation of most enzymes, especially PKC, until 12 wk, but was less effective by 20 wk. The oxidative inactivation of PKC, particularly its activated form that translocated to the membrane fraction, was confirmed in the in vitro exposure to active oxygen generators at an optimal concentration; this inactivation was prevented by catalase and superoxide dismutase. These results suggested that the formation of Ox-LDL and alterations in CE-metabolizing enzymes caused by passive smoking could contribute to a twofold increase in the aortic CE content, thereby contributing to one of the mechanisms for atherosclerosis associated with smoking.
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PMID:Effects of passive smoking on the regulation of rat aortic cholesteryl ester hydrolases by signal transduction. 1090 85

Oxidative stress is involved in the pathogenesis of various degenerative diseases including cancer. It is now recognized that low levels of oxidants can modify cell-signaling proteins and that these modifications have functional consequences. Identifying the target proteins for redox modification is key to understanding how oxidants mediate pathological processes such as tumor promotion. These proteins are also likely to be important targets for chemopreventive antioxidants, which are known to block signaling induced by oxidants and to induce their own actions. Various antioxidant preventive agents also inhibit PKC-dependent cellular responses. Therefore, PKC is a logical candidate for redox modification by oxidants and antioxidants that may in part determine their cancer-promoting and anticancer activities, respectively. PKCs contain unique structural features that are susceptible to oxidative modification. The N-terminal regulatory domain contains zinc-binding, cysteine-rich motifs that are readily oxidized by peroxide. When oxidized, the autoinhibitory function of the regulatory domain is compromised and, consequently, cellular PKC activity is stimulated. The C-terminal catalytic domain contains several reactive cysteines that are targets for various chemopreventive antioxidants such as selenocompounds, polyphenolic agents such as curcumin, and vitamin E analogues. Modification of these cysteines decreases cellular PKC activity. Thus the two domains of PKC respond differently to two different type of agents: oxidants selectively react with the regulatory domain, stimulate cellular PKC, and signal for tumor promotion and cell growth. In contrast, antioxidant chemopreventive agents react with the catalytic domain, inhibit cellular PKC activity, and thus interfere with the action of tumor promoters.
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PMID:Protein kinase C signaling and oxidative stress. 1092 54

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 oxidised low density lipoproteins. Some epidemiological studies have shown an association between high dietary intake or high serum concentrations of vitamin E and lower rates of ischemic heart disease. Recently, the Cambridge Heart Antioxidant Study (CHAOS) reported strong protection by high vitamin E doses against the risk of fatal and non fatal myocardial infarction. Here we have shown that incubation of vascular smooth muscle cells in the presence of alpha-tocopherol resulted in inhibition of cell proliferation and protein kinase C activity. Since beta-tocopherol and probucol are not inhibitory, the effect of alpha-tocopherol is considered due to a non-oxidant mechanism. In order to understand the protective role of alpha-tocopherol against atherosclerosis in vivo the following rabbit studies were carried out. Atherosclerosis was induced by a vitamin E poor diet containing 2% cholesterol in a group of rabbit. The other groups had 2% cholesterol in the diet plus 50 mg/kg vitamin E i.m. or 1% probucol or 50 mg/kg vitamin E plus 1% probucol. After 4 weeks, aortas were removed and analysed by microscopy for atherosclerotic lesions. Samples of the media were analysed for protein kinase C activity. The aortas of cholesterol-fed rabbits showed typical atherosclerotic lesions, detected by microscopic examination, their media smooth muscle cells exhibited an increase in protein kinase C activity. Vitamin E fully prevented cholesterol induced atherosclerotic lesions and the induction of protein kinase C activity while probucol was not effective. These results show that the protective effect of vitamin E against hypercholesterolemic atherosclerosis is not produced by an other antioxidant such as probucol and, therefore, may not be linked to the antioxidant properties of this vitamin. The effects observed at the level of smooth muscle cells in vitro and ex-vivo suggests an involvement of signal transduction events in the protective effect of vitamin E against atherosclerosis.
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PMID:Effect of vitamin E on the development of atherosclerosis. 1096 37

Platelet activation is tightly regulated by products of the endothelium and platelets including nitric oxide (NO). Excess vascular oxidative stress has been associated with impaired NO release, and antioxidant status has been shown to alter endothelium-derived NO bioactivity. Although physiological levels of a-tocopherol are known to inhibit platelet function, the effect of a-tocopherol on platelet NO release is unknown. Loading platelets with physiologic levels of a-tocopherol increased platelet NO production approximately 1.5-fold (Pa-tocopherol, platelet NO release increased 50% (Pa-Tocopherol-loaded platelets also produced 74% less superoxide as compared with control (Pa-tocopherol inhibited PKC-dependent eNOS phosphorylation as determined by immunoprecipitation. Lastly, platelets isolated from NOS3-deficient mice released 80% less superoxide as compared with control animals (P=0.011), and incubation of NOS III-deficient platelets with 500 mM a-tocopherol only caused a modest additional decrease in platelet superoxide release (NS). Thus, a-tocopherol appears to enhance platelet NO release both in vitro and in vivo through antioxidant- and PKC-dependent mechanisms.
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PMID:alpha-Tocopherol and protein kinase C inhibition enhance platelet-derived nitric oxide release. 1102 7

Animal and epidemiological studies suggest that polyphenol constituents of red wine possess antioxidant activities that favour protection against cardiovascular disease - the so-called. 'French paradox' - and possibly, central nervous system disorders such as Alzheimer's disease (AD) and ischaemia. In the present study, the potential of three major red wine derived-polyphenols to protect against toxicity induced by the nitric oxide free radical donors sodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1) was examined in cultured rat hippocampal cells. Both co- and post-treatments with either the stilbene resveratrol (5 - 25 microM) or the flavonoids quercetin (5 - 25 microM) and (+)-catechin (1 - 10 microM) were capable of attenuating hippocampal cell death and intracellular reactive oxygen species accumulation produced by SNP (100 microM and 1 mM, respectively). However, among the phenolic compounds tested, only the flavonoids afforded significant protection against 5 mM SIN-1-induced toxicity. The effects of phenolic constituents were shared by Trolox (100 microM), a vitamin E analogue, but not by selective inhibitors of cyclo-oxygenases (COX) and lipoxygenases (LOX). Among the phenolic compounds tested, only quercetin (10 microM) inhibited 100 microM SNP-stimulated protein kinase C (PKC) activation, whereas none of them were able to attenuate nitrite accumulation caused by SNP (100 microM). Taken together, these data suggest that the neuroprotective abilities of quercetin, resveratrol, and (+)-catechin result from their antioxidant properties rather than their purported inhibitory effects on intracellular enzymes such as COX, LOX, or nitric oxide synthase. Quercetin, however, may also act via PKC to produce its protective effects.
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PMID:Neuroprotective abilities of resveratrol and other red wine constituents against nitric oxide-related toxicity in cultured hippocampal neurons. 1103 Jul 20


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