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 (A) II is a potent constrictor as well as growth stimulant of vascular smooth muscle cell caused by activation of AT1 receptor signal transduction systems. There are two major signal systems of AT1 receptor: one leads to an increase in cytosolic free calcium levels causing smooth muscle contraction which may result in high blood pressure, and the other leads to smooth muscle proliferation and inflammation which may result in atherosclerosis. AT1 receptor activation induces phosphinositide hydrolysis by phospholipase C and creates an inositol phosphate, which release calcium from cytosolic calcium pools. Cytosolic calcium can also be elevated by activation of calcium channel via a link between AT1 receptor and a G protein. Protein phosphorylation triggered by AT1 receptor is important for cell growth, in which tyrosine kinase, serine/threonine kinase and protein kinase C are involved. Free radicals are generated by NADH/NADPH oxidase in response to AT1 receptor activation, causing expression of genes leading to atherosclerosis. On the other hand, activation of AT2 receptor is shown to play a role of lowering blood pressure. Some phosphatases and NO/cyclic GMP would be involved in the mechanism. In renal vasculature, endothelium dependent epoxygenase products are synthesized by AT2 receptor stimulation causing vasorelaxation. In summary, AT1 receptor signals are vasopressive and evoke atherosclerosis, whereas AT2 receptor signals may possibly be vasodilatory.
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PMID:[Signal transduction systems of angiotensin II receptors]. 1036 37

The aim of the present study was to investigate the proliferative effects of Ang II in human cardiac fibroblasts. The effects of Ang II in human cardiac fibroblasts on the 3H-thymidine incorporation, the cell number, the 3H-leucine incorporation and the total protein content were measured. The expression of receptor mRNA was performed by reverse transcription-polymerase chain reaction (RT-PCR). Ang II increased 3H-leucine incorporation in a concentration-dependent manner but not 3H-thymidine incorporation in primary cultures of human cardiac fibroblasts. The maximum effect (24 +/- 3% over control) was obtained at a concentration of 10 nM. There were no significant alterations of cell number or total protein content, suggesting that Ang II stimulated protein synthesis but did not induce hypertrophy. The accumulation of 3H-leucine was blocked by the AT1 receptor antagonist candesartan but not by the AT2 receptor antagonist PD123319. By using RT-PCR, both AT1 and AT2 receptors mRNA were found to be expressed in human cardiac fibroblasts. The selective MAPKK inhibitor PD098059, the protein kinase C inhibitor K252a or the phospholipase C inhibitor U73122 did not significantly inhibit Ang II augmented 3H-leucine incorporation. However, this was significantly blocked by the Ca2+-dependent protein kinase C inhibitor GO6976, the non-selective protein kinase inhibitor staurosporine and the tyrosine kinase inhibitor tyrphostin 25. The effects of Ang II were unaffected by the Gi-protein blocker pertussis toxin, indicating a Gi-protein-independent pathway. Ang II was synergistic with insulin but showed no significant increase on 3H-leucine incorporation when combined with PDGF or EGF. In summary, Ang II stimulates protein synthesis through AT1 receptors in human cardiac fibroblasts, but has no hypertrophic or hyperplastic effect. The response is mediated by a MAPKK-independent and Ca2+-sensitive PKC-dependent pathway.
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PMID:Angiotensin II type 1 receptors stimulate protein synthesis in human cardiac fibroblasts via a Ca2+-sensitive PKC-dependent tyrosine kinase pathway. 1071 68

We investigated the ganglionic effects of angiotensin II (Ang II) and the signal transduction involved in the cardiac sympathetic ganglia by the direct administration of agents to the ganglia through the right subclavian artery and monitoring the heart rate as an indicator of the ganglionic function in pithed dogs. Ang II given i.a. caused increases in the heart rate, which was inhibited by the treatment with the AT1-receptor antagonist forasartan, but not by the AT2-receptor antagonist PD-123319. The stimulation by Ang II, but not by acetylcholine, was inhibited after treatment with an inhibitor of phospholipase C, U-73122; a cell-permeant modulator of the Ins(1,4,5)P3 receptors, 2-aminoethoxydiphenyl borate; an intracellular calcium and calcium-associated protein kinase inhibitor, HA-1077; calmodulin (CaM) inhibitor, W-7; Ca2+/CaM-dependent protein kinase II inhibitor, KN-93; a selective protein kinase C inhibitor, calphostin C; and Na+H+ exchange inhibitor, dimethylamiloride. These results suggest that Ang II stimulates the ganglionic transmission at postsynaptic sites via the activation of AT1 receptor coupled to either activation of phospholipase C, phosphoinositide hydrolysis and subsequent increase in intracellular Ca2+ and activation of protein kinase C and Ca2+/CaM kinase II, although this ganglionic stimulation seems to involve, at least in part, the protein kinases-dependent increase of amiloride-sensitive Na+ inflow.
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PMID:Possible involvement of calcium-calmodulin pathways in the positive chronotropic response to angiotensin II on the canine cardiac sympathetic ganglia. 1156 11

We assessed the effects of the angiotensin II (Ang II) type 1 receptor (AT1-receptor) blocker, candesartan, (CN, 1 mg/kg i.v. over 30 minutes pre-ischaemia) alone or after intracoronary administration of Ang II type 2 receptor (AT2-receptor) blocker (PD 123319), protein kinase C (PKC) inhibitor (chelerythrine), endothelial nitric oxide (NO) synthase inhibitor (N(G)-monomethyl-L-arginine or L-NMMA), and bradykinin (BK) -B2 receptor inhibitor (HOE140) on in vivo left ventricular (LV) function and remodelling (echocardiograms/Doppler) and haemodynamics in 30 dogs with reperfused anterior infarction (90 minutes ischaemia, 120 minutes reperfusion), and ex vivo infarct size, AT1-receptor/AT2-receptor proteins and PKC(epsilon) (immunoblots), and cyclic guanosine 3', 5' monophosphate (cGMP, immunoassay). Compared with controls, CN inhibited the Ang II pressor response, reduced LV preload, improved LV systolic and diastolic function, limited LV remodelling, decreased infarct size, and increased AT2-receptor and PKC(epsilon) proteins in the infarct zone (IZ), and these responses were abrogated by PD 123319, chelerythrine, L-NMMA and HOE140. In addition, the increase in LV cGMP with CN was attenuated by PD 123319, L-NMMA and HOE140. The overall results suggest that AT2-receptor activation and signalling via BK, PKC(epsilon) and cGMP contribute to cardioprotection associated with AT1-receptor blockade during ischaemia-reperfusion injury.
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PMID:Enhanced regional AT(2)-receptor and PKC(epsilon) expression during cardioprotection induced by AT(1)-receptor blockade after reperfused myocardial infarction. 1188 Nov 13

Studies were performed to compare the actions of Ang II in the internal anal sphincter (IAS) vs. lower esophageal sphincter (LES) smooth muscles in vitro, in opossum and rabbit. Studies also were carried out in isolated smooth muscle cells. In opossum, Ang II produced no discernible effects in the IAS, but did produce a concentration-dependent contraction in the LES. Conversely, in the rabbit, while Ang II caused a modest response in the LES, it caused a significant contraction in the IAS. The contractile responses of Ang II in the opossum LES were mostly resistant to different neurohumoral antagonists but were antagonized by AT1 antagonist losartan. AT2 antagonist PD 123,319, rather than inhibiting, prolonged the contractile action of Ang II. The contractile actions of Ang II in the opossum LES were not modified by the tyrosine kinase inhibitors (genistein and tyrphostin 1 x 10(-6) M) but were partially attenuated by the PKC inhibitor H-7 (1 x 10(-6) M), Ca2+ channel blocker nicardipine (1 x 10(-5) M), Rho kinase inhibitor HA-1077 (1 x 10(-7) M) or p(44/42) MAP kinase inhibitor PD 98059 (5 x 10(-5) M). The combination of HA-1077 and H-7 did not cause an additive attenuation of Ang II responses. Western blot analyses revealed the presence of both AT1 and AT2 receptors. We conclude that Ang lI-induced contraction of sphincteric smooth muscle occurs primarily by the activation of AT1 receptors at the smooth muscle cells and involves multiple pathways, influx of Ca2+, and PKC, Rho kinase and p(44/42) MAP kinase.
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PMID:Comparison of angiotensin II (Ang II) effects in the internal anal sphincter (IAS) and lower esophageal sphincter smooth muscles. 1200 7

Metabolism of arachidonic acid through cyclooxygenase, lipoxygenase, or P450 epoxygenase pathways leads to the formation of various bioactive eicosanoids. In this review, we discuss alterations in expression pattern of eicosanoid-generating enzymes found during prostate tumor progression and expound upon their involvement in tumor cell proliferation, apoptosis, motility, and tumor angiogenesis. The expression of cyclooxygenase-2, 12-lipoxygenase, and 15-lipoxygenase-1 are up-regulated during prostate cancer progression. It has been demonstrated that inhibitors of cyclooxygenase-2, 5-lipoxygenase and 12-lipoxygenase cause tumor cell apoptosis, reduce tumor cell motility and invasiveness, or decrease tumor angiogenesis and growth. The eicosanoid product of 12-lipoxygenase, 12(S)-hydroeicosatetraenoic acid, is found to activate Erkl/2 kinases in LNCaP cells and PKCalpha in rat prostate AT2.1 tumor cells. Overexpression of 12-lipoxygenase and 15-lipoxygenase-1 in prostate cancer cells stimulate prostate tumor angiogenesis and growth, suggesting a facilitative role for 12-lipoxygenase and 15-lipoxygenase-1 in prostate tumor progression. The expression of 15-lipoxygenase-2 is found frequently to be lost during the initiation and progression of prostate tumors. 15(S)-hydroxyeicosatetraenoic acid, the product of 15-lipoxygenase-2, inhibits proliferation and causes apoptosis in human prostate cancer cells, suggesting an inhibitory role for 15-lipoxygenase-2 in prostate tumor progression. The regulation of prostate cancer progression by eicosanoids, in either positive or negative ways, provides an exciting possibility for management of this disease.
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PMID:Role of eicosanoids in prostate cancer progression. 1208 62

Angiotensin II (Ang II) is a multifunctional hormone that influences the function of cardiovascular cells through a complex series of intracellular signaling events initiated by the interaction of Ang II with AT1 and AT2 receptors. AT1 receptor activation leads to cell growth, vascular contraction, inflammatory responses and salt and water retention, whereas AT2 receptors induce apoptosis, vasodilation and natriuresis. These effects are mediated via complex, interacting signaling pathways involving stimulation of PLC and Ca2+ mobilization; activation of PLD, PLA2, PKC, MAP kinases and NAD(P)H oxidase, and stimulation of gene transcription. In addition, Ang II activates many intracellular tyrosine kinases that play a role in growth signaling and inflammation, such as Src, Pyk2, p130Cas, FAK and JAK/STAT. These events may be direct or indirect via transactivation of tyrosine kinase receptors, including PDGFR, EGFR and IGFR. Ang II induces a multitude of actions in various tissues, and the signaling events following occupancy and activation of Ang receptors are tightly controlled and extremely complex. Alterations of these highly regulated signaling pathways may be pivotal in structural and functional abnormalities that underlie pathological processes in cardiovascular diseases such as cardiac hypertrophy, hypertension and atherosclerosis.
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PMID:Recent advances in angiotensin II signaling. 1221 72

Angiotensin II (Ang II) receptor subtype 1, AT1, is expressed by the rat thyroid. A relationship between thyroid function and several components of the renin-angiotensin system has also been established, but the Ang II cellular effects in thyrocytes and its transduction signalling remain undefined. The aim of the present paper was to investigate the modulation of the activity of the Na(+)-K(+)ATPase by Ang II and its intracellular transduction pathway in PC-Cl3 cells, an established epithelial cell line derived from rat thyroid. Here we have demonstrated, by RT-PCR analysis, the expression of mRNA for the Ang II AT1 receptor in PC-Cl3 cells; mRNA for the Ang II AT2 receptor was not detected. Ang II was not able to affect the intracellular Ca(2+) concentration in fura-2-loaded cells, but it stimulated the translocation from the cytosol to the plasma membrane of atypical protein kinase C-zeta (PKC-zeta) and -iota (PKC-) isoforms with subsequent phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK1 and 2). Translocated atypical PKCs displayed temporally different activations, the activation of PKC-zeta being the fastest. PC-Cl3 cells stimulated with increasing Ang II concentrations showed dose- and time-dependent activation of the Na(+)-K(+)ATPase activity, which paralleled the PKC-zeta translocation time course. Na(+)-K(+)ATPase activity modulation was dependent on PKC activation since the PKC antagonist staurosporine abolished the stimulatory effect of Ang II. The inhibition of the ERK kinases 1 and 2 (MEK1 and 2) by PD098059 (2'-amino-3'-methoxyflavone) failed to block the effect of Ang II on the Na(+)-K(+)ATPase activity. In conclusion, our results suggest that Ang II modulates Na(+)-K(+)ATPase activity in PC-Cl3 cells through the AT1 receptor via activation of atypical PKC-zeta while the Ang II-activated PKC- appears to have other as yet unknown functions.
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PMID:Angiotensin II AT1 receptor stimulates Na+ -K+ATPase activity through a pathway involving PKC-zeta in rat thyroid cells. 1252 32

In cardiac myocytes, sarcolemmal Na+/H+ exchanger (NHE) activity is subject to regulation by a variety of G protein-coupled receptor (GPCR) systems. This regulation usually manifests as an increase in NHE activity (e.g. in response to the stimulation of alpha1-adrenergic, angiotensin AT1, endothelin and thrombin receptors), although some GPCR systems have been shown to inhibit sarcolemmal NHE activity (e.g. beta1-adrenergic receptors) or to attenuate its stimulation by other ligands (e.g. adenosine A1 and angiotensin AT2 receptors). The pertinent molecular signalling mechanisms are only now beginning to be unravelled, with the extracellular signal regulated kinase/ribosomal S6 kinase pathway and the protein kinase C pathway both appearing to play critical roles in the stimulation of sarcolemmal NHE activity. GPCR-mediated regulation of sarcolemmal NHE activity is likely to play significant roles in modulating myocardial function in both physiological and pathophysiological conditions. These roles include the regulation of (1) myocardial pH(i) and contractility, (2) myocardial susceptibility to injury and dysfunction during ischaemia and reperfusion, and (3) myocardial hypertrophy in response to neurohormonal and mechanical stimuli. Greater understanding of the pertinent molecular signalling mechanisms distal to GPCR stimulation may reveal novel targets for therapeutic manipulation.
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PMID:Regulatory effects of G protein-coupled receptors on cardiac sarcolemmal Na+/H+ exchanger activity: signalling and significance. 1265 Aug 72

Differential activation of PKC isoforms by angiotensin II (AII) has been found in a variety of tissues in which this important octapeptide mediates its multitude of effects. To date, the PKC isoforms involved in mediating brain-specific effects are yet to be defined. In the present study, the identity of PKC isoforms coupled to AII stimulation was examined in the neuroblastoma X glioma hybrid cell line, NG108-15, by Western blot analysis. This cell line expresses both the AT1 and AT2 receptor subtypes, with the AT1 subtype predominating, and expression levels highly-upregulated when cells are in the differentiated state. Six PKC isoforms were examined in the present study, including three Ca(2+) dependent (alpha, beta, and gamma), and three Ca(2+) independent (delta, and zeta) isoforms. NG108-15 cells were found to express PKC alpha, delta, and zeta isoforms but not beta or gamma isoforms. Differential sensitivity of the PKC isoforms to AII stimulation was demonstrated, with AII causing a rapid and transient activation of the PKC alpha only in undifferentiated cells, whereas both PKC alpha and isoforms were responsive in differentiated cells. PKC activation was found to be both dose- and time-dependent. The data demonstrate the differential activation of PKC isoforms to AII stimulation in NG108-15 cells, with evidence supporting the involvement of the PKC alpha and isoforms in AII-mediated effects in the brain.
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PMID:Selective activation of protein kinase C isoforms by angiotensin II in neuroblastoma X glioma cells. 1506 66


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