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 effects of phorbol ester, phorbol 12-myristate 13-acetate (PMA), on vasodilation induced by endothelium-dependent or independent vasodilators in the mesenteric arterial bed were examined. In mesentery precontracted with methoxamine, acetylcholine (ACh) produced a concentration-dependent vasodilation, but ACh-induced vasodilation was significantly reduced when the tonus of the mesentery was raised by an equieffective concentration of PMA. Sodium nitroprusside (SNP) and forskolin also caused a concentration-dependent relaxation in the mesenteric arterial bed pre-contracted with methoxamine, but could not induce relaxation in mesentery precontracted with PMA. In mesentery precontracted with PMA or methoxamine, ACh-induced vasodilation was significantly inhibited by tetraethylammonium (TEA), but not by ouabain, glibenclamide, or apamin. ACh-induced vasodilation was significantly inhibited by NG-nitro-L-arginine (L-NNA), whereas L-NNA was not capable of effectively inhibiting the ACh-induced vasodilation of the mesentery precontracted with PMA. These results suggest that stimulation of protein kinase C (PKC) by phorbol ester (PMA) in the mesenteric arterial bed inhibits the relaxation of vascular smooth muscle (VSM) in response to cyclic nucleotides. Furthermore, the endothelium of the mesenteric arterial bed may release endothelium-derived hyperpolarizing factor (EDHF), in addition to nitric oxide (NO), into the mesentery.
J Cardiovasc Pharmacol 1995 Oct
PMID:Effects of phorbol ester on vasodilation induced by endothelium-dependent or endothelium-independent vasodilators in the mesenteric arterial bed. 856 28

Protein kinases play important roles in intracellular signalling pathways in probably all cells. In the heart, they are involved in the regulation of ion handling, contractility, fuel metabolism and growth. In this review, we discuss the consequences of activation of protein kinases known to be expressed in the heart. We concentrate principally on the following: cyclic AMP-dependent protein kinase, protein kinase C, mitogen-activated protein kinase, Ca2+/calmodulin-dependent protein kinases and pyruvate dehydrogenase kinase.
Cardiovasc Res 1995 Oct
PMID:Intracellular signalling through protein kinases in the heart. 857 96

In this review, the angiotensin-II-mediated signal transduction pathways involved in vascular smooth muscle cell growth are discussed. Classical pathways involving phospholipase C and protein kinase C, as well as the mitogen-activated protein kinase pathway, are common signal transduction pathways activated by a variety of growth factors to stimulate cell growth. Besides its vasoconstrictor activity, angiotensin II stimulates hypertrophy of vascular smooth muscle cells and is involved in neointimal proliferation following balloon angioplasty. Understanding angiotensin-II-stimulated signaling events, as well as the crosstalk among signaling pathways, may form the basis for the development of new therapies for hypertension and restenosis.
Cardiovasc Res 1995 Oct
PMID:Angiotensin II signal transduction and the mitogen-activated protein kinase pathway. 857 99

Cardiac fibroblasts appear to be important in producing and maintaining the extracellular matrix (ECM) of the heart. The abnormal proliferation of cardiac fibroblasts and deposition of the ECM protein, collagen, associated with hypertension and myocardial infarction, may adversely affect the performance of the heart. Several groups of factors affect collagen gene expression and/or growth of cardiac fibroblasts. Angiotensin II, aldosterone and endothelins play a central role in the remodeling of the ECM in hypertension, and decrease collagenase activity and/or increase collagen synthesis in cultured cells. Regulatory peptides that are generally elevated at sites of injury, such as TGF-beta 1 and PDGF, increase collagen synthesis and/or stimulate mitogenesis. Mechanical stretch enhances collagen expression and cell proliferation, responses which could in part be due to integrin activation. Cytokines may stimulate or inhibit cell growth, the latter through prostaglandin formation. Angiotensin II is a principal determinant in vivo of cardiac fibroplasia and synthesis of the ECM proteins, collagen and fibronectin. Cardiac fibroblasts possess G-protein-coupled AT1 receptors for angiotensin II that couple to activation of multiple signalling pathways, including: phospholipase C-beta, with the subsequent release of Ca2+ from intracellular stores and activation of protein kinase C, mitogen-activated protein kinases, tyrosine kinases, phospholipase D, phosphatidic acid formation, and the STAT family of transcription factors. Cardiac fibroblasts respond to angiotensin II with hyperplastic/hypertrophic growth, and increased expression of collagen, fibronectin, and integrins. The mechanisms by which the AT1 receptor activates multiple signalling pathways are not known, although the receptor might interact at some level with both integrins and cytokine receptors. Different signalling pathways of the AT1 receptor may subserve different cellular responses, such as mitogenesis, ECM synthesis, or an inflammatory/stress response. Crosstalk among the signalling pathways of the AT1 receptor, and those of G-protein, cytokine, and growth-factor receptors, may determine the ultimate response of the cell.
Cardiovasc Res 1995 Oct
PMID:Molecular signalling mechanisms controlling growth and function of cardiac fibroblasts. 857 2

We have previously demonstrated that stimulation of cultured rat neonatal cardiomyocytes by endothelin-1 (ET-1) induces rapid activation of phospholipase C-beta (PLC-beta), accompanied by transient expression of proto-oncogenes and subsequent development of hypertrophy and characteristic phenotypic changes. In the present study we examined the ET-1-induced hypertrophic response in relation to the initial signaling by phospholipase D (PLD) and protein kinase C (PKC). ET-1 (10(-8) M) induced hypertrophy after 48 h, as judged by protein/DNA ratio. The formation (0.5 h) of 14C-labeled phosphatidylethanol ([14C]PEth) in the presence of exogenous ethanol (0.5%) in [14C]palmitate prelabeled cells, which reflects the PLD activity, was increased 1.9- and 5.6-fold by ET-1 and phorbolester (PMA, 10(-6) M), respectively. The translocation of PKC isoforms from the cytosol to the membrane fraction was examined by immunoblot analysis using specific antibodies for PKC-alpha and -epsilon. ET-1 caused a rapid (within 15 s) and sustained disappearance of PKC-epsilon but not of PKC-alpha, from the cytosol. The translocation of PKC-epsilon to the membrane fraction was just detectable. However, PMA (10(-7) M) showed a rapid, sustained, and clearly detectable translocation of PKC-alpha and PKC-epsilon. The results indicate that the ET-1-induced development of hypertrophy via activation of distinct PKC isoenzymes may be initiated not only by PLC-beta but also by PLD signaling.
J Cardiovasc Pharmacol 1995
PMID:Endothelin-1-induced phospholipase C-beta and D and protein kinase C isoenzyme signaling leading to hypertrophy in rat cardiomyocytes. 858 31

In estrogen-treated rat myometrium, endothelin-1 (ET-1) activated both the phospholipase C (PLC) which degrades PtdInsP2, resulting in an increased accumulation of inositol phosphates, and the phospholipase D pathway (PLD) as evidenced in the presence of butanol by an increased production of phosphatidylbutanol (PBut). Both ET-1 effects displayed similar concentration dependencies (EC50 50 nM) and were mediated by ET(A) receptors in that they were antagonized by BQ123 and were elicited by ET-3 with a rank order of potency ET-1 >> ET-3. Bombesin, another activator of the PLC/PtdInsP2 pathway, also increased PBut accumulation. Enhanced production of PBut could also be observed with the Ca2+ ionophore ionomycin and the phorbol ester PMA, an activator of protein kinase C, suggesting a potential contribution of the PLC/PtdInsP2 pathway in ET-1 induced PLD activity.
J Cardiovasc Pharmacol 1995
PMID:ETA receptors mediate activation of phospholipases C and D in rat myometrium. 858 97

We studied whether endothelin (ET)-1 regulates its own transcription in cultured rat aortic endothelial cells (ECs) in an autocrine manner and attempted to elucidate its cellular and molecular mechanism. By Northern blot analysis using rat preproET-1 cDNA as a probe, ET-1 increased steady-state levels of preproET-1 mRNA as early as 30 min, which persisted during 4 h incubation. ET-1 also increased steady-state c-fos mRNA levels, which returned to an undetectable level by 2 h. ET-1 dose-dependently upregulated preproET-1 mRNA expression. The effect was inhibited by nonselective ETA/ETB receptor antagonist but not a selective ETA receptor antagonist. The ET-1-induced preproET-1 mRNA expression was suppressed by a protein kinase C (PKC) inhibitor and by pretreatment with phorbol ester, which depeleted engdogenous PKC. The approximate half-life of preproET-1 mRNA stimulated by ET-1 (approximately 20 min) was similar to that stimulated by phorbol ester. Our data demonstrate that ET-1 upregulates its own gene expression through ETB receptor-mediated PKC activation, suggesting a possible autocrine positive feedback system in vascular endothelium.
J Cardiovasc Pharmacol 1995
PMID:Autocrine regulation of the endothelin-1 gene in rat endothelial cells. 858 76

We assessed the role of protein kinase C (PKC) in the mechanism responsible for the potentiation of UK-14304-induced contractions produced when isolated dog mesenteric vascular rings were pretreated with threshold concentrations of 12-O-tetradecanoyl-phorbol-13-acetate (TPA), KCl, or endothelin-1 (ET-1). In dog mesenteric artery. UK-14304 produced a biphasic concentration-response curve in the presence of TPA, KCl, or ET-1, with the curve portion at lower concentrations being alpha 2-adrenoceptor dependent and the portion at higher concentrations being alpha 1-adrenoceptor dependent. Calphostin C (10(-6)M), a PKC inhibitor, abolished amplified UK-14304-induced contraction in the TPA-pretreated tissues. In the KCl- and ET-1-pretreated tissues. 10(-6)M calphostin C antagonized amplified UK-14304-induced contractions by approximately 20% in both parts of the concentration-response curve. In contrast, in dog mesenteric vein, amplified UK-14304-induced contractions by TPA, KCl, and ET-1 were entirely dependent on alpha 2-adrenoceptors. Calphostin C (10(-6)M), which in control experiments had no effect on KCl-induced contraction and antagonized responses to TPA by 60.1%, inhibited UK-14304-induced contraction by 18.3%. Amplified UK-14304-induced contraction was antagonized by 10(-6)M calphostin C by 21.8% in KCl-precontracted tissues, 58.1% in ET-1-precontracted tissues, and 66.3% in TPA-precontracted tissues. In the ET-1- and TPA-pretreated dog mesenteric veins, 10(-6)M calphostin C decreased maximal tensions of enhanced UK-14304-induced contractions to the same level as the UK-14304-induced maximal tension inhibited by 10(-6)M calphostin C in untreated dog mesenteric vein. Therefore, TPA can be a precontracting agent that amplifies UK-14304-induced contractions through PKC activation in both dog mesenteric artery and vein. PKC predominantly mediates the contraction amplification mechanisms after exposure to ET-1 in dog mesenteric vein and does not play a major role in the amplification of UK-14304-induced contraction by KCl in both dog mesenteric artery and vein. These data show that a common mechanism need not underlie amplification of adrenergic responses in mesenteric artery and vein.
J Cardiovasc Pharmacol 1995 Dec
PMID:Activation of protein kinase C as a modulator of potentiated UK-14304-induced contractions in dog mesenteric artery and vein. 860 29

To clarify the pathophysiological significance of endothelin (ET) in the ischemic myocardium, we examined the effect of endothelin-1 (ET-1) on the ATP-sensitive K+ current (IK.ATP) and compared it with that of ET-3 in guinea pig ventricular cells using conventional microelectrode and patch clamp techniques. In isolated guinea pig papillary muscles, ET-1 (30 nM) markedly increased developed tension (DT), with little influence on action potential duration (APD), whereas ET-3 at the same concentration failed to affect DT or APD. Both nicorandil (1 mM) and cromakalim (30 microM) markedly shortened APD and decreased DT in papillary muscles. ET-1, but not ET-3, partially reversed the nicorandil-induced decreases in APD and DT in a concentration-dependent manner. ET-1 also attenuated the cromakalim-induced decreases in APD and DT. In single ventricular myocytes, both nicorandil and cromakalim increased a steady-state outward current, which was sensitive to 1 microM glibenclamide, suggesting that these drugs activate IK.ATP. ET-1 (30 nM) significantly inhibited the IK.ATP, whereas ET-3 failed to affect it. The ET-1 induced inhibition of IK.ATP was abolished by BQ-485 (100 nM), an ETA receptor-selective antagonist. Neither the protein kinase C (PKC) inhibitor staurosporine (20 nM) nor the calmodulin antagonist W-7 (50 microM) affected the inhibitory action of ET-1 on the nicorandil-induced IK.ATP. In pertussis toxin (PTX)-treated cells, the inhibitory action of ET-1 on IK.ATP was augmented rather than attenuated. These results suggest that ET-1 partially inhibits the IK.ATP through the activation of ETA receptors, although the precise intracellular mechanism remains to be clarified. Because activation of the ATP-sensitive K+ channels is considered to protect the ischemic myocardium, the partial inhibition of IK.ATP by ET-1 may lead to the aggravation of myocardial injury, potentially due to an increase in transmembrane Ca2+ influx.
J Cardiovasc Pharmacol 1996 Jan
PMID:Endothelin-1 partially inhibits ATP-sensitive K+ current in guinea pig ventricular cells. 865 45

Since protein kinase C (PKC) has been proven to be a mediator of neutrophil activation and of intracellular calcium homeostasis, its inhibition could protect the myocardium from the deleterious effects of ischemic/reperfusion inury (IRI). The principal objective of this study was to evaluate the efficacy of the PK inhibitor SPC-100270 (2S,3S)-2-amino, 3-octadecanediol in a canine model of IRI. A double-blind study was conducted in which 19 coonhound dogs received either SPC-100270 or a vehicle before going on cardiopulmonary bypass (CPB). After 60 minutes of global normothermic (37 degree C) cardiac arrest (cross-clamp time 65-81 minutes for SPC-100270 and 65-72 minutes for control) and discontinuation of CBP, an epicardial short axis view echocardiogram was performed and reviewed by a double-blinded observer to determine the ejection fraction (EF). EF value exceeded 20% in 5 out of 9 SPC-100270 animals (27%-44%) and in 0 of 10 controls (0%-16%). These data show that SPC-10027 significantly (p=0.01 by Fisher's Exact Test) increased the probability that the animals would exhibit an EF greater than 20%.
J Cardiovasc Surg (Torino) 1996 Apr
PMID:Pre-clamp cardioprotection by protein kinase C (PKC) inhibitor improves left ventricular function following canine normothermic arrest. 867 19


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