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)

The purposes of this study were to determine whether ischemic preconditioning (IPC) in human atrial trabeculae is mediated by alpha 1-adrenoceptors and protein kinase C (PKC) and whether the protection of IPC is replicated with alpha 1-adrenoceptor stimulation [alpha 1-adrenoceptor preconditioning (alpha 1-PC)]. Atrial trabeculae were obtained during coronary bypass surgery. The trabeculae were suspended in organ baths containing Tyrode solution and field stimulated at 1 Hz, and developed force was recorded. The trabeculae underwent 45 min of simulated ischemia (SI) and 120 min of reperfusion (I/R injury). IPC trabeculae received transient SI before I/R injury, alpha 1-Adrenoceptor blockade with BE-2254 and PKC inhibition with chelerythrine were independently combined with IPC before I/R injury. alpha 1-PC before I/R was examined with alpha 1-adrenergic agonist (phenylephrine) pre-treatment. Improved recovery of developed force and higher tissue creatine kinase activity were present in IPC trabeculae, and the protective effect of IPC was eliminated with either alpha 1-adrenoceptor blockade or PKC inhibition. alpha 1-PC trabeculae also exhibited enhanced functional recovery after I/R injury but lacked preservation of tissue creatine kinase activity. PKC inhibition eliminated the functional protection of alpha 1-PC. These results suggest that, in human atrial trabeculae, alpha 1-adrenoceptors and PKC mediate, in part, the functional and tissue CK preservation conferred by IPC, but alpha 1-PC does not replicate the protection of IPC.
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PMID:Ischemic preconditioning of human myocardium: protein kinase C mediates a permissive role for alpha 1-adrenoceptors. 927 9

Recent studies have indicated that repeated brief episodes of ischemia and reperfusion render the myocardium more tolerant to subsequent lethal ischemic injury. In view of the previous observations that ischemia-reperfusion potentiates phospholipase D signaling and that such signaling is beneficial for the heart, we investigated whether a similar phospholipase D signaling is responsible for the beneficial effects associated with repeated ischemia and reperfusion. Using an isolated perfused working rat heart model, we demonstrated that four brief episodes of 5 min of ischemia and 10 min of reperfusion reduced the incidence of ventricular arrhythmias, enhanced the postischemic ventricular performance, and decreased the release of creatine kinase from the reperfused heart, with simultaneous activation of phospholipase D generating the second messengers diacylglycerol and phosphatidic acid and leading to the translocation and activation of protein kinase C. The specific antiphospholipase D antibody blocked the activation of phospholipase D and attenuated the generation of diacylglycerol and phosphatidic acid and activation of protein kinase C. In concert, phospholipase D inhibition increased the incidence of ventricular arrhythmias, blocked the beneficial effects of preconditioning on the ventricular performance, and increased the amount of creatine kinase release from the coronary effluent. The results of this study indicate that repeated brief episodes of ischemia and reperfusion exert beneficial effects on the intact rat heart by triggering the activation of a phospholipase D signaling mechanism.
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PMID:Ischemic preconditioning triggers phospholipase D signaling in rat heart. 936 54

We investigated whether parathyroid hormone-related peptide (PTH-rP), recently found expressed in the heart, exerts growth and contractile effects on adult cardiomyocytes from rat hearts. Synthetic PTH-rP peptides were used covering either a protein kinase C (PKC)-activating domain [PTH-rP(107-111)], or an adenylate cyclase activating domain [PTH-rP(1-34) and PTH-rP(7-34)]. PTH-rP(107-111) (1 micro M) increased creatine kinase BB activity (CK-BB), a CK isoform re-expressed during cardiac hypertrophy, within 24 h by 62+/-12%. This induction was abolished in the presence of the mitogen-activated-protein (MAP)-kinase-kinase inhibitor PD 98059. PTH-rP(107-111) activated p42-MAP-kinase within 15 min, increased protein synthesis (19+/- 4%), total protein mass (19+/-5%), cell volume (45+/-7%), and cross-sectional area (38+/-9%) of cardiomyocytes. Activation of p42-MAP-kinase and increase in protein synthesis were abolished in presence of bisindolylmaleimide, a PKC inhibitor. PTH- rP(107-111) did not directly influence contractile activity but reduced the contractile response to isoprenaline. In contrast, PTH-rP(1-34) and PTH-rP(7-34) induced spontaneous contractile activity in 3-day-old cultures. This induction was abolished in presence of Rp-cAMPS, a protein kinase A inhibitor, indicating an involvement of cAMP in this response. PTH-rP(1-34) also increased the cellular accumulation of cAMP. It is concluded that PTH-rP exert direct effects on adult cardiomyocytes by activating either PKC via a functional domain covered by amino acids 107-111 or by activation of cAMP-dependent protein kinase via a functional domain covered by amino acids 7-34. Since these parts of PTH-rP have either no homology [PTH-rP(107-111)] or only a limited structural similarity [PTH-rP(7-34)] to parathyroid hormone, these activities of PTH-rP have to be clearly distinguished from those described for parathyroid hormone.
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PMID:Effects of PTH-rP(107-111) and PTH-rP(7-34) on adult cardiomyocytes. 940 80

In addition to decreasing the incidence of myocardial infarction, recent epidemiological data suggest that regular alcohol consumption improves survival after myocardial infarction. We recently found that chronic ethanol exposure induces long-term protection against cardiac ischemia-reperfusion injury, which improves myocardial recovery after infarction. Furthermore, this cardioprotection by ethanol is mediated through myocyte adenosine A1 receptors. We now determine the role of protein kinase C (PKC) in ethanol's protective effect against ischemia-reperfusion injury. Using perfused hearts of ethanol-fed guinea pigs, we find that improved contractile recovery and creatine kinase release after ischemia-reperfusion are abolished by PKC inhibition with chelerythrine. Western blot analysis and immunofluorescence localization demonstrate that regular ethanol consumption causes sustained translocation (activation) of epsilonPKC, but not delta or alphaPKC. This same isozyme is directly implicated in ischemic preconditioning's protection against ischemia-reperfusion injury. Our findings suggest (i) that regular ethanol consumption induces long-term cardioprotection through sustained translocation of epsilonPKC and (ii) that PKC activity is necessary at the time of ischemia to mediate ethanol's protective effect against ischemia-reperfusion injury. Studying this selective effect of ethanol on epsilonPKC activation may lead to new therapies to protect against ischemia-reperfusion injury in the heart and other organ systems.
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PMID:Activation of epsilon protein kinase C correlates with a cardioprotective effect of regular ethanol consumption. 965 75

Signal transduction pathways involved in the hypertrophic effect of neuropeptide Y (NPY) were investigated in adult cardiomyocytes. Reduction of transforming growth factor-beta activity in serum-supplemented media abolished the induction of hypertrophic responsiveness to NPY. In responsive cells, NPY (100 nM) increased protein synthesis, determined as incorporation of [14C]phenylalanine, by 35 +/- 15% (P < 0.05, n = 16 cultures). In these cells, NPY activated pertussis toxin (PTx)-sensitive G proteins and phosphatidylinositol (PI) 3-kinase. PTx and inhibition of PI 3-kinase abolished the hypertrophic effect of NPY. NPY also activated protein kinase C (PKC) and mitogen-activated protein (MAP) kinase. Inhibition of these two kinases attenuated the induction of creatine kinase (CK)-BB but not the growth response to NPY. In conclusion, NPY stimulates protein synthesis in adult cardiomyocytes via activation of PTx-sensitive G proteins and PI 3-kinase and it induces the fetal-type CK-BB via activation of PKC and MAP kinase.
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PMID:Intracellular signaling leads to the hypertrophic effect of neuropeptide Y. 981 68

Ischemic preconditioning (I-PC) occurs via activation of protein kinase C (PKC). This study was undertaken to determine whether pharmacologic preconditioning by beta-adrenergic stimulation (beta-PC) is mediated by PKC activation. Isolated rat hearts were subjected to 40-min ischemia and 30-min reperfusion. Beta-PC was induced by 0.25 microM isoproterenol pretreatment for 2 min followed by 10-min normoxic perfusion. Beta-PC enhanced the recovery of rate-pressure product of the ischemic/reperfused heart (79.1 +/- 8.4% vs. 12.4 +/- 1.6% of initial for Non-PC group, n = 6) and attenuated the release of creatine kinase during 30-min reperfusion (30.2 +/- 2.2 vs. 59.8 +/- 6.1 nmol/min/g wet wt for Non-PC group, n = 6), similar to an I-PC stimulus of 5-min ischemia and 5-min reperfusion. Treatment with 50 microM polymyxin B, a PKC inhibitor, abolished the cardioprotection of both beta-PC and I-PC. Furthermore, similar changes in subcellular distribution of PKC were induced by both beta-PC and I-PC. The changes in subcellular distribution of PKC-delta suggested its translocation from cytosol to membrane fraction, a marker of PKC activation. These results suggest that the cardioprotection induced by beta-PC, like I-PC, is mediated by PKC activation.
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PMID:Pharmacologic preconditioning induced by beta-adrenergic stimulation is mediated by activation of protein kinase C. 986 2

There is evidence involving protein kinase C (PKC) in the signal transduction pathways that regulate the differentiation of myoblasts into mature multinucleated muscle cells (myotubes). In order to obtain information on the possible role of individual PKC isozymes in myogenesis, in the present work we investigated the differential expression of PKC isoforms alpha, beta, delta, epsilon, and zeta during muscle cell development in vitro. Chick embryo myoblasts cultured from 1 to 6 days were used as experimental model. Morphological characterization and measurement of specific biochemical parameters in cultures, e.g., DNA synthesis, creatine kinase activity, and myosin levels, revealed a typical muscle cell developmental pattern consisting of an initial proliferation of myoblasts followed by their differentiation into myotubes. PKC activity was high at the proliferation stage, decreased as myoblasts elongated and fused, and increased again in differentiated myotubes. In proliferating myoblasts, the PKC inhibitors calphostin C and bisindolylmaleimide I decreased DNA synthesis whereas in myoblasts undergoing differentiation they exerted the opposite effect, suggesting that PKC plays a role at both stages of myogenesis. Western blot analysis of changes in the expression of PKC isoforms during muscle cell development showed high levels of PKC alpha in the proliferating phase which markedly decreased as myoblasts differentiated. Treatment with TPA of proliferative myoblasts inhibited DNA synthesis and selectively down-regulated PKC alpha, suggesting that this isozyme may have an important role in maintaining myoblast proliferation. On the other hand, an increase in the expression of PKC beta, delta, and epsilon was detected during myogenesis, suggesting that one or more of these isoforms may participate in the differentiation process of myoblasts.
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PMID:Evidence on the participation of protein kinase C alpha in the proliferation of cultured myoblasts. 1040 97

Changes in morphology and DNA synthesis in cultured myoblasts in response to 1,25-dihydroxy-vitamin D3 [1,25(OH)2D3] have previously suggested that the vitamin D hormone may affect muscle cell proliferation and differentiation. However, this interpretation was not substantiated by measurement of specific biochemical markers of myogenesis. To study the effect of 1,25(OH)2D3 on muscle development, chicken embryo myoblasts were cultured for 1-6 days in the presence or absence of 1,25(OH)2D3 (10(-9) M). The hormone increased DNA synthesis and decreased creatine kinase activity, indicating stimulation of cell proliferation and inhibition of myogenesis, in undifferentiated myoblasts (1 day of culture). At longer culture intervals, when myoblasts elongate and fuse to form differentiated myotubes, 1,25(OH)2D3 promoted myogenesis, as indicated by an inhibition of DNA synthesis and an increase in specific muscle differentiation markers as creatine kinase activity and myosin expression. The role of protein kinase C (PKC) in mediating the effects of hormone and the likely PKC isoform involved were also investigated. Increased PKC activity was observed during 1,25(OH)2D3 stimulation of myoblast proliferation whereas inhibition of PKC activity accompanied the effects of the hormone on myoblast differentiation. The specific PKC inhibitor calphostin suppressed hormone potentiation of DNA synthesis in proliferating myoblasts. 1,25(OH)2D3-dependent changes in the expression of PKC isoforms alpha, beta, delta, epsilon and zeta during myogenesis were investigated by Western blot analysis. The early stimulation of myoblast proliferation by the hormone mainly correlated to increased PKC alpha expression whereas decreased PKC alpha levels were observed during the subsequent activation of myoblast differentiation. These results support that 1,25(OH)2D3 has a function in embryonic muscle growth and maturation, and PKC alpha may participate in the signal transduction pathway which mediates the response to the hormone.
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PMID:Participation of protein kinase C alpha in 1,25-dihydroxy-vitamin D3 regulation of chick myoblast proliferation and differentiation. 1045 52

Myocardial ischemia results in an increase in intracellular sodium concentration ([Na]i), which may lead to cellular injury via cellular swelling and calcium overload. Because protein kinase C (PKC) has been shown to reduce Na-K-ATPase activity, we postulated that pharmacological inhibition of PKC would directly increase Na-K-ATPase activity, reduce [Na]i during ischemia, and provide protection from ischemic injury. Isolated rat hearts were subjected to 30 min of global ischemia with and without the specific PKC inhibitor chelerythrine. Intracellular pH, ATP, and [Na]i were assessed using 31P and 23Na NMR spectroscopy, whereas Na-K-ATPase and PKC activity were determined using biochemical assays. Na/H exchanger activity was determined using the ammonium prepulse technique under nonischemic conditions. Chelerythrine increased Na-K-ATPase activity (13.76 +/- 0.89 vs. 10.89 +/- 0.80 mg ADP. h(-1). mg protein(-1); P = 0.01), reduced PKC activity in both the membrane and cytosolic fractions (39% and 28% of control, respectively), and reduced creatine kinase release on reperfusion (48 +/- 5 IU/g dry wt vs. 689 +/- 63 IU/g dry wt; P = 0.008). The rise in [Na](i) during ischemia was significantly reduced in hearts treated with chelerythrine (peak [Na](i) chelerythrine: 21.5 +/- 1.2 mM; control: 31.9 +/- 1.2 mM; P < 0.0001), without an effect on either acidosis (nadir pH 6.16 +/- 0.05 for chelerythrine vs. 6.08 +/- 0.04 for control), the rate of ATP depletion or Na/H exchanger activity. These data support the hypothesis that pharmacological inhibition of PKC before ischemia induces cardioprotection by reducing intracellular sodium overload via an increase in Na-K-ATPase activity.
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PMID:Chelerythrine increases Na-K-ATPase activity and limits ischemic injury in isolated rat hearts. 1048 22

Diadenosine tetraphosphate (AP4A) administration is reported to mimic the effect of ischemic preconditioning (PC) via purine 2y receptors (P2yR) and adenosine receptors. This study was designed to test the contributions of the ATP-sensitive potassium channel (KATP channel) and protein kinase C (PKC), two of the main regulator in PC, to the effect of AP4A. Isolated buffer-perfused rat hearts were subjected to 20 min of global ischemia (37 degrees C) and 20 min of reperfusion. Three cycles of 1-min ischemia and 3-min reperfusion induced PC. Chemicals were administrated for 2 min before 20 min of ischemia. AP4A (10 microM) administration was as effective as PC in improving the recovery of post-ischemic contractile function and reducing creatine kinase leakage after reperfusion, whereas adenosine (10 and 100 microM) have not effect. AP4A had not effect on reperfusion-induced arrhythmia, whereas PC significantly prevented it. These effects of AP4A and PC were reversed by co-administration of glibenclimade (KATP channel blocker, 100 microM) and GF109203X (PKC inhibitor, 10 microM); the effects of AP4A but not PC were reversed by co-administration of reactive blue (P2yR antagonist, 13 nM). AP4A appears to activate the KATP channel and PKC via P2yR mimic the effects of PC in part. The role of P2yR indicated that trigger mechanism of the effect of PC and AP4A administration might differ in rat hearts.
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PMID:Diadenosine tetraphosphate (AP4A) mimics cardioprotective effect of ischemic preconditioning in the rat heart: contribution of KATP channel and PKC. 1087 25


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