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)

Several studies demonstrated an inverse association between polyphenol intake and cardiovascular events. Platelet recruitment is an important phase of platelet activation at the site of vascular injury, but it has never been investigated whether polyphenols influence platelet recruitment. The aim of the study was to analyze in vitro whether two polyphenols, quercetin and catechin, were able to affect platelet recruitment. Platelet recruitment was reduced by NO donors and by NADPH oxidase inhibitors and was enhanced by L-NAME, an inhibitor of NO synthase. Quercetin and catechin, but not single polyphenol, significantly inhibited platelet recruitment in a concentration-dependent fashion. The formation of superoxide anion was significantly inhibited in platelets incubated with quercetin and catechin but was unaffected by a single polyphenol. Incubation of platelets with quercetin and catechin resulted in inhibition of PKC and NADPH oxidase activation. Treatment of platelets with quercetin and catechin resulted in an increase of NO and also down-regulated the expression of GpIIb/IIIa glycoprotein. This study shows that the polyphenols quercetin and catechin synergistically act in reducing platelet recruitment via inhibition of PKC-dependent NADPH oxidase activation. This effect, resulting in NO-mediated platelet glycoprotein GpIIb/IIIa down-regulation, could provide a novel mechanism through which polyphenols reduce cardiovascular disease.
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PMID:Polyphenols enhance platelet nitric oxide by inhibiting protein kinase C-dependent NADPH oxidase activation: effect on platelet recruitment. 1677 7

Modulation of Ca(2+)-activated K(+) channels (K(Ca)) has been implicated in the control of proliferation in vascular smooth muscle cells (VSMC) and other cell types. In the present study, we investigated the underlying signal transduction mechanisms leading to mitogen-induced alterations in the expression pattern of intermediate-conductance K(Ca) in VSMC. Regulation of expression of IK(Ca)/rK(Ca)3.1 and BK(Ca)/rK(Ca)1.1 in A7r5 cells, a cell line derived from rat aortic VSMC, was investigated by patch-clamp technique, quantitative RT-PCR, immunoblotting procedures, and siRNA strategy.PDGF stimulation for 2 and 48 h induced an 11- and 3.5-fold increase in rK(Ca)3.1 transcript levels resulting in a four- and seven-fold increase in IK(Ca) currents after 4 and 48 h, respectively. Upregulation of rK(Ca)3.1 transcript levels and channel function required phosphorylation of extracellular signal-regulated kinases (ERK1/2) and Ca(2+) mobilization, but not activation of p38-MAP kinase, c-Jun NH(2)-terminal kinase, protein kinase C, calcium-calmodulin kinase II and Src kinases. In contrast to rK(Ca)3.1, mRNA expression and functions of BK(Ca)/rK(Ca)1.1 were decreased by half following mitogenic stimulation. Downregulation of rK(Ca)1.1 did not require ERK1/2 phosphorylation or Ca(2+) mobilization. In an in vitro-proliferation assay, knockdown of rK(Ca)3.1 expression by siRNA completely abolished functional IK(Ca) channels and mitogenesis. Mitogen-induced upregulation of rK(Ca)3.1 expression is mediated via activation of the Raf/MEK- and ERK-signaling cascade in a Ca(2+)-dependent manner. Upregulation of rK(Ca)3.1 promotes VSMC proliferation and may thus represent a pharmacological target in cardiovascular disease states characterized by abnormal cell proliferation.
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PMID:Mitogenic modulation of Ca2+ -activated K+ channels in proliferating A7r5 vascular smooth muscle cells. 1677 Mar 24

Endothelial NO synthase (eNOS) is the predominant enzyme responsible for vascular NO synthesis. A functional eNOS transfers electrons from NADPH to its heme center, where L-arginine is oxidized to L-citrulline and NO. Common conditions predisposing to atherosclerosis, such as hypertension, hypercholesterolemia, diabetes mellitus and smoking, are associated with enhanced production of reactive oxygen species (ROS) and reduced amounts of bioactive NO in the vessel wall. NADPH oxidases represent major sources of ROS in cardiovascular pathophysiology. NADPH oxidase-derived superoxide avidly interacts with eNOS-derived NO to form peroxynitrite (ONOO(-)), which oxidizes the essential NOS cofactor (6R-)5,6,7,8-tetrahydrobiopterin (BH(4)). As a consequence, oxygen reduction uncouples from NO synthesis, thereby rendering NOS to a superoxide-producing pro-atherosclerotic enzyme. Supplementation with BH(4) corrects eNOS dysfunction in several animal models and in patients. Administration of high local doses of the antioxidant L-ascorbic acid (vitamin C) improves endothelial function, whereas large-scale clinical trials do not support a strong role for oral vitamin C and/or E in reducing cardiovascular disease. Statins, angiotensin-converting enzyme inhibitors and AT1 receptor blockers have the potential of reducing vascular oxidative stress. Finally, novel approaches are being tested to block pathways leading to oxidative stress (e.g. protein kinase C) or to upregulate antioxidant enzymes.
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PMID:Janus-faced role of endothelial NO synthase in vascular disease: uncoupling of oxygen reduction from NO synthesis and its pharmacological reversal. 1713 97

Sex hormone status has emerged as an important modulator of coronary physiology and cardiovascular disease risk in both males and females. Our previous studies have demonstrated that testosterone increases protein kinase C (PKC) delta expression and activity in coronary smooth muscle (CSMC). Because PKCdelta has been implicated in regulation of proliferation and apoptosis in other cell types, we sought to determine if testosterone modulates CSMC proliferation and/or apoptosis through PKCdelta. Porcine CSMC cultures (passages 2-6) from castrated males were treated with testosterone for 24 h. Testosterone (20 and 100 nM) decreased [(3)H]thymidine incorporation in proliferating CSMC to 59 +/- 5.3 and 33.1 +/- 4.5% of control. Flow cytometric analysis demonstrated that testosterone induced G(1) arrest in CSMC with a concomitant reduction in the S phase cells. Testosterone reduced protein levels of cyclins D(1) and E and phosphorylation of retinoblastoma protein while elevating levels of p21(cip1) and p27(kip1). There were no significant differences in the levels of cyclins D(3), CDK2, CDK4, or CDK6. Testosterone significantly reduced kinase activity of CDK2 and -6, but not CDK4, -7, or -1. PKCdelta small interfering RNA (siRNA) prevented testosterone-mediated G(1) arrest, p21(cip1) upregulation, and cyclin D(1) and E downregulation. Furthermore, testosterone increased CSMC apoptosis in a dose-dependent manner, which was blocked by either PKCdelta siRNA or caspase 3 inhibition. These findings demonstrate that the anti-proliferative, pro-apoptotic effects of testosterone on CSMCs are substantially mediated by PKCdelta.
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PMID:PKCdelta mediates anti-proliferative, pro-apoptic effects of testosterone on coronary smooth muscle. 1750 29

Diabetes mellitus is a chronic disease caused by inherited and/or acquired deficiency in production of insulin by the pancreas, and by resistance to insulin's effects. Such a deficiency results in increased concentrations of glucose and other metabolites in the blood, which in turn damages many of the body's systems, in particular the eyes, kidneys, nerves, heart and blood vessels. There are two major types of diabetes mellitus: Type 1 diabetes (insulin-dependent diabetes, IDDM or juvenile onset diabetes) and Type 2 diabetes (non-insulin-dependent diabetes, NIDDM or adult-onset). Chronic hyperglycemia is a major initiator of diabetic micro- and cardiovascular complications, such as retinopathy, neuropathy and nephropathy. Several hyperglycemia-induced mechanisms may induce vascular dysfunctions, which include increased polyol pathway flux, altered cellular redox state, increased formation of diacylglycerol (DAG) and the subsequent activation of protein kinase C (PKC) isoforms and accelerated non-enzymatic formation of advanced glycated end products. It is likely that each of these mechanisms may contribute to the known pathophysiologic features of diabetic complications. Others and we have shown that activation of the DAG-PKC pathway is associated with many vascular abnormalities in the retinal, renal, neural and cardiovascular tissues in diabetes mellitus. DAG-PKC pathway affects cardiovascular function in many ways, such as the regulation of endothelial permeability, vasoconstriction, extracellular matrix (ECM) synthesis/turnover, cell growth, angiogenesis, cytokine activation and leucocyte adhesion, to name a few. Increased DAG levels and PKC activity, especially alpha, beta1/2 and delta isoforms in retina, aorta, heart, renal glomeruli and circulating macrophages have been reported in diabetes. Increased PKC activation have been associated with changes in blood flow, basement membrane thickening, extracellular matrix expansion, increases in vascular permeability, abnormal angiogenesis, excessive apoptosis and changes in enzymatic activity alterations such as Na(+)-K(+)-ATPase, cPLA(2), PI3Kinase and MAP kinase. Inhibition of PKC, especially the beta1/2 isoform has been reported to prevent or normalize many vascular abnormalities in the tissues described above. Clinical studies have shown that ruboxistaurin, a PKCbeta isoform selective inhibitor, normalize endothelial dysfunction, renal glomerular filtration rate and prevented loss of visual acuity in diabetic patients. Thus, PKC activation involving several isoforms is likely to be responsible for some of the pathologies in diabetic retinopathy, nephropathy and cardiovascular disease. PKC isoform selective inhibitors are likely new therapeutics, which can delay the onset or stop the progression of diabetic vascular disease with very little side effects.
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PMID:The role of protein kinase C activation and the vascular complications of diabetes. 1757 31

Numerous reports on the molecular mechanism of atherogenesis indicate an increase in oxidative stress, formation of advanced glycoxidation end products (AGEs), chronic inflammation, and activated cellular response particularly in diabetic patients. To elucidate the initiating and early accelerating events this review will focus on the molecular causes of the induction of these stress factors, their interactions, and their contribution to atherogenesis. Metabolic factors such as elevated free fatty acids, high glucose levels or AGEs induce reactive oxygen species (ROS) in vascular cells leading to ongoing AGE formation and to gene induction of proinflammatory cytokines. Vice versa, numerous cytokines found elevated in obesity and diabetes may also induce oxidative stress thus a circulus vitious may be initiated and accelerated. Increased production of ROS, mainly from mitochondria and NAD(P)H oxidase, stimulates signaling cascades including protein kinase C and mitogen-activated protein kinase pathway leading to nuclear translocation of transcription factors such as nuclear factor-kappaB (NF-kappaB), activator protein 1, and specificity protein 1. Subsequently, the expression of numerous genes including cytokines is rapidly induced, which, in turn, may act on vascular cells promoting the deleterious effects. From animal models of accelerated atherosclerosis a causal role of NAD(P)H oxidase and the AGE/RAGE/NF-kappaB axis to atherogenesis is suggested. Because all factors involved form a highly interwoven network of interactions, the blockade of ROS or AGE formation at different sites may interrupt the vicious cycle. Promising candidate agents are, currently on trial. Most important to clinical practice, a number of drugs commonly used in the treatment of diabetes, hypertension, or cardiovascular disease, such as angiotensin-converting enzyme inhibitors, AT(1) receptor blockers, 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins), and thiazolidindiones have shown promising 'preventive' intracellular antioxidant activity in addition to their primary pharmacological actions.
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PMID:Oxidative stress, AGE, and atherosclerosis. 1765 6

Endothelial dysfunction is universal in diabetes, being intimately involved with the development of cardiovascular disease. The pathogenesis of endothelial dysfunction in diabetes is complex. It is initially related to the effects of fatty acids and insulin resistance on 'uncoupling' of both endothelial nitric oxide synthase activity and mitochondrial function. Oxidative stress activates protein kinase C (PKC), polyol, hexosamine and nuclear factor kappa B pathways, thereby aggravating endothelial dysfunction. Improvements in endothelial function in the peripheral circulation in diabetes have been demonstrated with monotherapies, including statins, fibrates, angiotensin-converting enzyme (ACE) inhibitors, metformin and fish oils. These observations are supported by large clinical end point trials. Other studies show benefits with certain antioxidants, L-arginine, folate, PKC-inhibitors, peroxisome proliferator activated receptor (PPAR)-alpha and -gamma agonists and phosphodiesterase (PDE-5) inhibitors. However, the benefits of these agents remain to be shown in clinical end point trials. Combination treatments, for example, statins plus ACE inhibitors and statins plus fibrates, have also been demonstrated to have additive benefits on endothelial function in diabetes, but there are no clinical outcome data to date. Measurement of endothelial dysfunction in cardiovascular research can provide fresh opportunities for exploring the mechanism of benefit of new therapeutic regimens and for planning and designing large clinical trials.
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PMID:Therapeutic regulation of endothelial dysfunction in type 2 diabetes mellitus. 1765 40

Cardiovascular disease is the leading cause of morbidity and mortality in industrial societies, with myocardial infarction as the primary assassin. Pharmacologic agents, including the myocardial cell membrane receptor agonists adenosine, bradykinin/angiotensin-converting enzyme inhibitors, opioids and erythropoietin or the mixed cell membrane and intracellular agonists, glucose insulin potassium, and volatile anesthetics, either clinically or experimentally reduce the extent of myocardial injury when administered just prior to reperfusion. Agents that specifically target proteins, transcription factors or ion channels, including PKC agonists/antagonists, PPAR, Phosphodiesterase-5 inhibitors, 3-Hydroxy-3-methyl glutaryl coenzyme A reductase and the ATP-dependent potassium channel are also promising. However, no agent has been specifically approved to reduce reperfusion injury clinically. In this review, we will discuss the advantages and limitations of agents to combat reperfusion injury, their market development status and findings reported in both clinical and preclinical studies. The molecular pathways activated by these agents that preserve myocardium from reperfusion injury, which appear to commonly involve glycogen synthase kinase 3beta and mitochondrial permeability transition pore inhibition, are also described.
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PMID:Pharmacologic therapeutics for cardiac reperfusion injury. 1787 67

To elucidate an anti-inflammatory role of angiotensin-converting enzyme inhibitors (ACEIs) in cardiovascular disease, we studied the effect of ACEIs in monocyte adhesion to endothelial cells and underlying molecular mechanisms. Treatment of human monocytic THP-1 cells with monocyte chemoattractant protein-1 (MCP-1; 100 ng/ml; 10 min) significantly increased their adhesion to human umbilical vein endothelial cells (HUVECs) under flow condition (P < 0.001). Preincubation of THP-1 cells with imidaprilat (50 nM; 4 h), an active metabolite of imidapril, reduced MCP-1-triggered THP-1 cell adhesion (P < 0.01). Similar effects were obtained with experiments using human peripheral monocytes (P < 0.05). MCP-1 activated protein kinase C (PKC)alpha in THP-1 cells, resulting in the up-regulation of alpha4 and beta2 integrin. Imidaprilat attenuated MCP-1-induced PKC activation and integrin up-regulation in THP-1 cells. Imidaprilat also inhibited THP-1 cell adhesion induced by phorbol 12-myristate 13-acetate (PMA), a potent PKC activator. In attempt to elucidate the mechanisms for the modulation of PKC activity by imidaprilat, we found that MCP-1 or PMA increased labile zinc in THP-1 cells, which was canceled by imidaprilat. Indeed, zinc/pyrithione activated PKC and increased THP-1 cell adhesion. Zinc chelator as well as PKC inhibitor inhibited these processes, suggesting the role for labile zinc in PKC activation and THP-1 cell adhesion. Imidaprilat attenuated zinc/pyrithione-induced PKC activation and THP-1 cell adhesion. These data suggest that ACEI reduces MCP-1 or PMA-triggered monocyte adhesion to activated HUVECs by modulating labile zinc in monocytes. Our findings may point out a novel anti-inflammatory mechanism of ACEIs in atherogenesis.
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PMID:Angiotensin-converting enzyme inhibitor attenuates monocyte adhesion to vascular endothelium through modulation of intracellular zinc. 1787 5

Platelets are central to haemostasis and thrombosis. Many key steps in platelet activation and aggregation are regulated by members of the PKC (protein kinase C) family. Multiple isoforms of PKC are expressed in platelets, and evidence is emerging that different isoforms play distinct roles in the platelet activation process. This may, in part, be regulated by isoform-specific interactions between PKC family members and other intracellular signalling molecules, such as tyrosine kinases, or the actin cytoskeleton regulator, VASP (vasodilator-stimulated phosphoprotein). The contributions of individual PKC isoforms can be addressed directly in platelets from knockout mouse models, which are providing key insights into the physiological function of PKC isoform diversity and can be a valuable complimentary approach to more commonly used pharmacological analyses. Using knockout mouse models, recent reports have demonstrated the importance of PKCbeta and PKCtheta in integrin-dependent platelet spreading, and also a novel role for PKCdelta in regulating filopodial formation, highlighting the utility of such models to investigate the functions of specific PKC isoforms in a physiological process that is significant to our understanding of cardiovascular disease.
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PMID:Isoform-specific functions of protein kinase C: the platelet paradigm. 1795 64


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