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)

Angiotensin-converting enzyme (ACE) plays an important role in the pathophysiology of cardiovascular disease. We investigated whether atorvastatin, a powerful agent for the prevention and treatment of cardiovascular disease, influences ACE production in endothelial cells. Human umbilical cord vein endothelial cells were treated with VEGF (476 pM), which induced ACE upregulation. Cotreatment with atorvastatin (0.1-10 microM) dose dependently inhibited VEGF-induced ACE upregulation. In the presence of mevalonate (100 microM), atorvastatin failed to downregulate VEGF-induced ACE production. Cotreatment of the cells with either farnesylpyrophosphate (FPP; 5 microM) or geranylgeranylpyrophosphate (GGPP; 5 microM) partially inhibited the suppressive effect of atorvastatin. Pretreatment of the cells with Rho-associated protein kinase inhibitor, Y-27632 (10 microM), partially inhibited VEGF-induced ACE upregulation. VEGF (476 pM) caused PKC phosphorylation, which was inhibited by cotreatment of the cells with atorvastatin. Atorvastatin inhibited VEGF-induced ACE upregulation probably by inhibiting PKC phosphorylation. This effect was mediated via inhibition of the mevalonate pathway. ACE downregulation may be an additional beneficial effect of statins in the treatment of cardiovascular disease.
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PMID:Atorvastatin completely inhibits VEGF-induced ACE upregulation in human endothelial cells. 1470 27

Twenty-four percent of the adult American population have the metabolic syndrome. Although somewhat counterintuitive, carefully regulated treatment with insulin has been shown to reduce insulin resistance and may also retard the development of cardiovascular disease by preventing chronic hyperglycemia, a condition that synergistically contributes to many proatherogenic pathways, including glycoxidation, the polyol pathway, advanced glycation end products, interference with normal metabolic pathways, and stimulation of protein kinase C-beta and proinflammatory pathways. This article describes some of the physiologic changes that occur when hyperglycemia and insulin resistance develop in patients with type 2 diabetes and discusses therapies, including insulin, that normalize glucose and reduce insulin resistance, thereby potentially reducing cardiovascular risk.
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PMID:Insulin therapy for reducing cardiovascular risk in patients with type 2 diabetes. 1498 5

Angiotensin-converting enzyme (ACE) plays an important role in the pathophysiology of cardiovascular disease. We examined the effect of carvedilol, a cardiovascular drug, on basal and stimulated ACE production in human endothelial cells. Carvedilol (0.625-5 microM), in a concentration-dependent manner, inhibited basal and vascular endothelial growth factor (VEGF, 0.5 nM) or phorbol 12-myristate 13-acetate (PMA, 10 nM) induced ACE up-regulation. Carvedilol has non-selective beta-adrenoceptor and selective alpha1-adrenoceptor blocking activity, calcium channel blocking, and anti-oxidant activity. To study whether these activities were related to ACE down-regulation, endothelial cells were treated with metoprolol (1-10 microM), propranolol (1-10 microM), prazosin (1-5 microM), nicardipine (1-10 microM), probucol (1-100 microM), or ascorbic acid (1-100 microM). None of these compounds modified ACE. VEGF (0.5 nM) and PMA (10 nM) induced PKC phosphorylation, which was inhibited by co-treatment of cell cultures with carvedilol (5 microM). In conclusion, carvedilol inhibited basal and VEGF or PMA induced ACE up-regulation. Inhibition of PKC phosphorylation was probably involved in carvedilol action.
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PMID:Carvedilol inhibits basal and stimulated ACE production in human endothelial cells. 1507 47

Chronic arsenic exposure is associated with an increased risk for cancer, cardiovascular disease (including ischemic heart disease and hypertension), peripheral vascular disease, and diabetes. Arsenic causes blood vessel growth and remodeling in vivo and cell specific, dose-dependent induction vascular endothelial growth factor-A (VEGF), which is essential for both processes. The current study examined the hypothesis that low, environmentally relevant levels of trivalent arsenic (AsIII) activate discrete signaling pathways in vascular smooth muscle cells (SMC) to induce expression of VEGF. AsIII caused a progressive increase in VEGF mRNA levels over a 48 h period in primary porcine SMC with a threshold of 1-2.5 microM. VEGF protein levels increased with a similar concentration dependence and time course. Hypoxia inducible factor-1alpha (HIF-1alpha) protein and mRNA levels also increased in response to AsIII. However, unlike the response to an iron chelator, AsIII-induced VEGF was not inhibited by siRNA directed toward HIF-1alpha. Instead, a novel protein kinase C, PKCdelta, was activated by AsIII to induce VEGF and stabilize HIF-1alpha. Consistent with this activation, AsIII caused coordinate increases in the levels of the intracellular second messenger diacyglycerol (DAG). These data suggest that AsIII induced divergent signaling pathways in SMCs that lead to independent increases in VEGF expression and HIF-1alpha signaling. However, these pathways both require initial increases in DAG levels and PKC activity.
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PMID:Signaling pathways for arsenic-stimulated vascular endothelial growth factor-a expression in primary vascular smooth muscle cells. 1508 98

Sex steroid hormones are involved in the metabolism, accumulation and distribution of adipose tissues. It is now known that oestrogen receptor, progesterone receptor and androgen receptor exist in adipose tissues, so their actions could be direct. Sex steroid hormones carry out their function in adipose tissues by both genomic and nongenomic mechanisms. In the genomic mechanism, the sex steroid hormone binds to its receptor and the steroid-receptor complex regulates the transcription of given genes. Leptin and lipoprotein lipase are two key proteins in adipose tissues that are regulated by transcriptional control with sex steroid hormones. In the nongenomic mechanism, the sex steroid hormone binds to its receptor in the plasma membrane, and second messengers are formed. This involves both the cAMP cascade and the phosphoinositide cascade. Activation of the cAMP cascade by sex steroid hormones would activate hormone-sensitive lipase leading to lipolysis in adipose tissues. In the phosphoinositide cascade, diacylglycerol and inositol 1,4,5-trisphosphate are formed as second messengers ultimately causing the activation of protein kinase C. Their activation appears to be involved in the control of preadipocyte proliferation and differentiation. In the presence of sex steroid hormones, a normal distribution of body fat exists, but with a decrease in sex steroid hormones, as occurs with ageing or gonadectomy, there is a tendency to increase central obesity, a major risk for cardiovascular disease, type 2 diabetes and certain cancers. Because sex steroid hormones regulate the amount and distribution of adipose tissues, they or adipose tissue-specific selective receptor modulators might be used to ameliorate obesity. In fact, hormone replacement therapy in postmenopausal women and testosterone replacement therapy in older men appear to reduce the degree of central obesity. However, these therapies have numerous side effects limiting their use, and selective receptor modulators of sex steroid hormones are needed that are more specific for adipose tissues with fewer side effects.
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PMID:Direct effects of sex steroid hormones on adipose tissues and obesity. 1545 95

Ca antagonists are relevant therapeutic tool for patients with hypertension. The effects of Ca antagonists against oxidative vascular damage and followed atherosclerosis were elucidated in various experimental model accompanied with the vasodilatative effects of Ca antagonists by blocking the L-type Ca channel. The beneficial effects of Ca antagonists in cardiovascular disease have been demonstrated in several clinical trials, as we demonstrated the beneficial effect of Ca antagonist in the incidence of cardiovascular event in Japanese patients with coronary disease. In patient with diabetes mellitus, the cardiovascular disease was also caused by the mechanism involved with the increase in oxidative stress in blood vessels and related factors such as advanced glycation endproducts, protein kinase C and insulin resistance. The beneficial effects of Ca antagonists in cardiovascular disease in patients with diabetes mellitus have been demonstrated in several clinical trials, may be dependent on the effect of Ca antagonist against the oxidative stress in the setting of hyperglycemia.
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PMID:[Effects of calcium channel blockers in atherosclerosis and cardiovascular event and oxidative vascular damage]. 1557 67

Low density lipoproteins (LDL) play important roles in the pathogenesis of atherosclerosis. Diabetes is associated with accelerated atherosclerosis leading to cardiovascular disease in diabetic patients. Although LDL stimulates the proliferation of arterial smooth muscle cells (SMC), the mechanisms are not fully understood. We examined the effects of native LDL and glycated LDL on the extracellular signal-regulated kinase (ERK) pathway. Addition of native and glycated LDL to rat aorta SMCs (RASMCs) stimulated ERK phosphorylation. ERK phosphorylation was not affected by exposure to the Ca2+ chelator BAPTA-AM but inhibition of protein kinase C (PKC) with GF109203X, inhibition of Src kinase with PP1 (5 microM) and inhibition of phospholipase C (PLC) with U73122/U73343 (5 microM) all reduced ERK phosphorylation in response to glycated LDL. In addition, pretreatment of the RASMCs with a cell-permeable mitogen-activated protein kinase kinase (MEK) inhibitor (PD98059, 5 microM) markedly decreased ERK phosphorylation in response to native and glycated LDL. These findings indicate that ERK phosphorylation in response to glycated LDL involves the activation of PKC, PLC, and MEK, but is independent of intracellular Ca2+.
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PMID:The Src/PLC/PKC/MEK/ERK signaling pathway is involved in aortic smooth muscle cell proliferation induced by glycated LDL. 1575 Mar 41

Cardiovascular disease is the leading cause of morbidity in Westernized populations. Low levels of alpha-tocopherol (AT) are associated with increased incidence of atherosclerosis and increased intakes appear to be protective. AT supplementation decreases interleukin 1 and 6 release from human monocytes. Thus, the aim of this study was to examine the effect of AT on an important proinflammatory cytokine, tumor necrosis factor-alpha (TNF) release from human monocytes. AT supplementation (1200 IU/day for 3 months) significantly decreased TNF release from activated human monocytes. Mechanisms that were examined included its effect as a general antioxidant, its inhibitory effect on protein kinase C (PKC), and the cycloxygenase-lipoxygenase pathway. While AT decreased TNF release from activated monocytes, other antioxidants had no effect on TNF release. Specific PKC inhibitors had no effect on TNF release from activated monocytes. The inhibition of TNF release by AT in activated monocytes was reversed by leukotriene B(4) (LTB(4)), a major product of the 5-lipoxygenase (5-LO) pathway. Similar observations were seen with inhibitors of 5-lipoxygenase. Indomethacin, a COX inhibitor, in the presence and absence of AT failed to affect TNF activity. These findings suggest that AT decreases TNF release from activated human monocytes via inhibition of 5-lipoxygenase. Also, AT as well as a 5-LO inhibitor significantly decreased TNF mRNA. Furthermore, AT and the 5-LO inhibitor decreased NFkappab-binding activity. Thus, in activated human monocytes, AT appears to inhibit TNF mRNA and protein by inhibition of 5-LO.
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PMID:Alpha-tocopherol decreases tumor necrosis factor-alpha mRNA and protein from activated human monocytes by inhibition of 5-lipoxygenase. 1580 19

Cardiovascular morbidity and mortality increase significantly with advancing age, with proportionally higher rates occurring in aged women when compared to aged men. The signaling alterations responsible for age-related reductions in ischemic stress reserves, particularly in aged women, are poorly understood. Accordingly, we sought to determine whether alterations in the cellular location and formation of specific protein kinase C (PKC)-extracellular regulated 1/2 (ERK1/2) signaling modules (SMS) might provide insight into known age- and sex-related differences in cardiovascular disease outcomes. Cytosolic (Cyto), mitochondrial (Mito) and nuclear (Nuc) fractions were isolated from left ventricles of male (M) and female (F) adult (6 mo), castrated or aged (23 mo) F344 rats by centrifugation. Western blotting was used to assess PKC (alpha, delta, epsilon), p-ERK1/2 and p-Bad(Ser112) levels, and immunoprecipitation to assess PKC-ERK1/2 SMS. Cyto-PKCalpha levels increased with age (p<0.0001), whereas increases in cyto-PKCalpha-ERK1/2 SMS were only observed in aged F (60%; p<0.01). Mito-PKCdelta and Mito-PKCdelta-ERK1/2 SMS increased in M and F with age (p<0.0001); however increases in Cyto-PKCdelta were only observed in aged M (80% p<0.0001). It is important to note that Nuc- and Mito-PKCdelta-ERK1/2 SMS were 3.5- and 4.8-fold greater in males versus females, respectively (p<0001). Increases in Mito-PKCepsilon-ERK1/2 SMS (216%) were also specific to aged M (p<0.0001), however, Mito-p-Bad(Ser112) levels were decreased with age in both M and F. Differences in sex hormone status could not fully account for observed age-related differences in PKC. Collectively, our results provide novel evidence for age and sex-related differences in the magnitude and distribution of cardiac PKC-ERK1/2 SMS consistent with previously described pathological and protective phenotypes, respectively.
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PMID:Age- and sex-dependent alterations in protein kinase C (PKC) and extracellular regulated kinase 1/2 (ERK1/2) in rat myocardium. 1581 23

Nitric oxide (NO) derived from endothelial NO synthase (eNOS) is a powerful vasodilator and possesses vasoprotective effects. Therefore, augmentation of eNOS expression and -activity by pharmacological means could provide protection against cardiovascular disease. However, this concept has been questioned recently, because in several disease models, eNOS upregulation was associated with a dysfunctional enzyme (referred to as eNOS uncoupling). In contrast, the present study demonstrates that an eNOS gene expression-enhancing compound with additional protein kinase C (PKC) inhibitory properties can upregulate eNOS while preserving its enzymatic function. Apolipoprotein E-knockout mice were treated for 7 days with midostaurin (4'-N-benzoyl staurosporine, compound CGP 41251, 50-125 mg/kg/day), a PKC inhibitor previously shown to increase eNOS expression and NO production in cultured human endothelial cells. Midostaurin treatment enhanced eNOS mRNA expression (RNase protection assay) in mouse aorta, kidney, and heart in a dose-dependent fashion. In the dorsal skinfold microcirculation, midostaurin produced an arteriolar vasorelaxation (intravital microscopy), which could be prevented by the NOS inhibitor L-NAME, indicating that the upregulated eNOS remained functional. In organ chamber experiments, the aorta from midostaurin-treated mice showed an enhanced NO-mediated relaxation in response to acetylcholine. Accordingly, serum levels of nitrite/nitrate (NO-Analyzer) were increased, and the production of reactive oxygen species in the aorta (L-012 chemiluminescence) was reduced by midostaurin. Thus, in mice in vivo, midostaurin treatment results in enhanced expression of eNOS with preserved enzyme function and enhanced production of bioactive NO. Given the beneficial effects of endothelial-derived NO, vasoprotective and anti-atherosclerotic effects are likely to ensue.
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PMID:Midostaurin upregulates eNOS gene expression and preserves eNOS function in the microcirculation of the mouse. 1589 May 50


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