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)

Recent evidence suggests that vasoconstrictive substances, including angiotensin II (Ang II), may function as a vascular smooth muscle growth promoting substance and may contribute to vascular hypertrophy in hypertension. Atrial natriuretic polypeptide (ANP) is known to be a physiological antagonist to Ang II in blood pressure and fluid homeostasis. Moreover, we have demonstrated that ANP can attenuate Ang II's action on vascular hypertrophy. In this study, we investigated the potential molecular mechanisms for the interaction of ANP and Ang II on vascular cell growth. Ang II dose-dependently induced RNA synthesis in post confluent cultured rat aortic smooth muscle (RASM) cells. ANP (10(-7) M) inhibited the hypertrophic effect of Ang II at the concentration of 10(-10) - 10(-8) M) but exerted no effect on the action of higher doses (10(-7) - 10(-6) M) of Ang II. Ang II (10(9) - 10(-8) M) and a protein kinase C activator, phorbol 12-myristate 13-acetate (PMA, 10(-8) M) rapidly induced c-fos as well as c-Jun and Jun-B mRNA expression in RASM cells. ANP (10(-7) M) itself had no apparent effect on the expression of these protooncogenes. Furthermore, ANP did not inhibit the induction of these protooncogenes by Ang II or PMA. Paradoxically, ANP (10(-7) M) significantly enhanced c-fos mRNA expression induced by Ang II and PMA. However, the chloramphenicol acetyl transferase (CAT) assay using a CAT expression vector containing the AP-1 binding element showed that ANP had no effect on the basal and PMA-stimulated AP-1 activity in transfected RASM cells. We conclude, therefore, that the inhibitory effect of ANP on the growth of vascular smooth muscle cells in vitro does not occur through the regulation of these protooncogene expressions.
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PMID:Interaction of atrial natriuretic polypeptide and angiotensin II on protooncogene expression and vascular cell growth. 182 53

Our previous studies have shown that angiotensin II (Ang II) has a dose-dependent biphasic effect on bicarbonate and sodium transport and 4-beta-phorbol-12-myristate-13-acetate can simulate the stimulatory effect of Ang II on Na+/H+ exchange in the proximal convoluted tubules (PCT) of the rat kidney. This study was designed to further investigate the possible role of phosphoinositide turnover in mediating the biphasic effect of Ang II. Rat PCT was perfused in vivo with Ringer's solution containing [3H]inulin as a volume marker. Bicarbonate flux (JHCO3) was determined by total CO2 changes between the collected fluid and the original perfusate as analyzed by microcalorimetry. Luminal perfusion with 10(-11) M Ang II or 10(-8) M 4-beta-phorbol-12-myristate-13-acetate stimulated both fluid reabsorption (JV) and JHCO3, these effects can be blocked by 2 x 10(-4) M 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8), a blocker of intracellular calcium mobilization. Interestingly, Ang II at 10(-9) M or 2 x 10(-4) M TMB-8 have no effect on JV or JHCO3 individually. However, JV and JHCO3 significantly decreased when PCT were perfused simultaneously with 10(-9) M Ang II and 10(-4) M 1-(5-isoquinolinesulfonyl)-2-methylpiperazine; whereas JV and JHCO3 significantly increased when PCT were perfused with 10(-9) M Ang II and 2 x 10(-4) M TMB-8 together. These results suggest that PKC and intracellular calcium play a critical role in mediating the biphasic effect of Ang II on bicarbonate and sodium transport in PCT.
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PMID:The role of phosphoinositide turnover in mediating the biphasic effect of angiotensin II on renal tubular transport. 184 21

We have previously shown that recombinant interleukin 1 (IL-1) and recombinant tumour necrosis factor (TNF) synergistically stimulate phospholipase A2 release from mesangial cells. We now report that treatment of mesangial cells with the beta-agonist salbutamol, prostaglandin E2 (PGE2), cholera toxin or forskolin, which all activate adenylate cyclase, increased release of phospholipase A2 activity. Likewise, addition of a membrane-permeant cyclic AMP (cAMP) analogue or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine enhanced release of phospholipase A2 activity from mesangial cells. There was a lag period of about 8 h before a significantly enhanced secretion could be detected. Furthermore, actinomycin D or cycloheximide completely suppressed cAMP-stimulated secretion of phospholipase A2. Angiotensin II, the phorbol ester phorbol 12-myristate 13-acetate, the Ca2+ ionophore A23187 and a membrane-permeant cGMP analogue did not stimulate phospholipase A2 release from the cells. Treatment with indomethacin completely inhibited IL-1 beta- and TNF-stimulated PGE2 synthesis, without having any effect on phospholipase A2 secretion, thus excluding cytokine-induced PGE2 synthesis as the mediator of phospholipase A2 release. Neither IL-1 beta nor TNF induced any increase in intracellular cAMP in mesangial cells. Furthermore, incubation of the cells with 2',5'-dideoxyadenosine, an inhibitor of adenylate cyclase, did not block cytokine-stimulated phospholipase A2 secretion. In addition, IL-1 beta and TNF synergistically interacted with forskolin to stimulate phospholipase A2 release from the cells. The protein kinase inhibitors H-8, staurosporine, K252a and amiloride inhibited IL-1 beta- and TNF-stimulated phospholipase A2 secretion. However, high concentrations that inhibit other protein kinases were needed. These observations suggest that IL-1 beta and TNF cause secretion of phospholipase A2 by a mechanism independent of cAMP. The signalling pathways used by IL-1 beta and TNF may involve a protein kinase that is probably different from protein kinase A or protein kinase C.
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PMID:Cyclic AMP mimics, but does not mediate, interleukin-1- and tumour-necrosis-factor-stimulated phospholipase A2 secretion from rat renal mesangial cells. 184 28

The purpose of this study was to test the hypothesis that angiotensin II (ang II) affects the transport of inorganic phosphate in adult ventricular myocytes. Ventricular myocytes were isolated from Dahl rats and allowed to take up 32P inorganic phosphate (32P-Pi). The intracellular 32P concentration increased rapidly and reached a peak at 5 min. Ang II, 10(-10) to 10(-5) M, produced a significant (P less than 0.05) and concentration-dependent reduction in 32P-Pi uptake that plateaued at 0.1 to 1.0 microM. Ang II at 1 microM produced a 30% reduction in Vmax and a slightly greater reduction in the Km of 32P-Pi uptake, compared to myocytes that were not exposed to ang II. The ang II receptor antagonist saralasin (Sar1-Val5-Ala8-angiotensin II), significantly (P less than 0.05) antagonized the action of ang II on 32P-Pi uptake. TPA (12-O-tetradecanoylphorbol-13-acetate) also produced a significant (P less than 0.05) reduction of 32P-Pi uptake, suggesting that protein kinase C is involved in the transduction of ang II effects on intracellular Pi. 32P Efflux from myocytes, pulsed with 32P-Pi and chased with Pi-free medium, was accentuated markedly by ang II; this effect was blunted by saralasin. These data suggest that ang II is capable of regulating total intracellular Pi in the heart via two actions: (i) by inhibiting uptake of Pi into the myocyte, and (ii) by increasing the efflux of phosphates out of the cell.
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PMID:Regulation by angiotensin II of phosphate transport in cardiac myocytes. 187 96

Angiotensin II (ANG II) plays an important role in the regulation of renal vascular resistance, glomerular function and tubular reabsorption. Systemic infusion of ANG II produces dose-dependent decreases in renal blood flow (RBF), glomerular filtration rate (GFR) and filtration coefficient, and increases in filtration fraction. Intrarenally generated ANG II is also critical to alterations in cortical and juxtamedullary glomerular ultrafiltration. On the other hand, pharmacological blockade of the systemical and intrarenal generation or action of ANG II elicits increases in RBF and pressure-associated changes in GFR. In vivo micropuncture experiments demonstrate that peritubular capillary microperfusion of 10(-7) M ANG II results in decreases in single nephron GFR and glomerular capillary pressure. Blockade of ANG II activity by ANG converting enzyme (ACE) inhibitor markedly attenuates, whereas intravenous or peritubular capillary infusion of exogenous ANG II enhances tubuloglomerular feedback (TGF) mediated changes in the stop flow pressure. Moreover, infusion of exogenous ANG II during conditions of ACE blockade partially restores the feedback responsiveness, suggesting a specific role of ANG II as a modulator of TGF system. Besides its effects on intrarenal hemodynamics, ANG II directly or indirectly affects renal sodium excretion. Micropuncture and microperfusion studies have shown that ANG II exerts a dose-dependent biphasic effect on proximal tubular sodium reabsorption via apical Na(+)-H+ exchange. A stimulatory effects of ANG II at low dose (10(-12)-10(-9) M) and an inhibitory effect at higher dose (10(-7)-10(-5) M) have been observed in the cortical and juxtamedullary nephron preparations. The stimulatory effect of ANG II on proximal tubular reabsorption of sodium seems associated with reduction in cAMP and/or activation of protein kinase C, whereas cytosolic free calcium surge activated by ANG II may be part of the cellular message that inhibits proximal tubular reabsorptive function. ANG III, a metabolite of ANG II, also enters substantial influence on renal function. In contrast to the systemic pressor effect, the two peptides are approximately equipotent in their actions on the renal vasculature. Superimposed administration of either ANG II or ANG III during ACE inhibition completely reverses the GFR and renal excretory responses to ACE inhibition. Furthermore, intracerebroventricular injections of ANG II and ANG III in rats inhibit renal nerve activity and cause a comparable renal effect which can be blocked by Ile7-ANG III and potentiated by bestatin, suggesting that the heptapeptide may also play an active role in the regulation of sodium excretion by actions on renal hemodynamics and tubules.
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PMID:Renal hemodynamic and tubular effects of angiotensins II and III. 187 31

Angiotensin II acts on adrenal glomerulosa cells to induce the phospholipase C-mediated generation of inositol trisphosphate and sn-1,2-diacylglycerol as the major products of inositol phospholipid breakdown. This last product is known to activate protein kinase C, but its role in the action of angiotensin II on steroidogenesis has not been defined. We report herein that, in bovine adrenal glomerulosa cells, protein kinase C activators, such as phorbol 12,13-dibutyrate, 12-O-tetradecanoylphorbol-13-acetate, mezerein and sn 1,2 oleoyl acetoylglycerol, each failed to increase steroidogenesis. These results contrast with our recent report on the enhancement of aldosterone output by sn-1,2-dioctanoylglycerol (DiC8) [J. Steroid Biochem. 35 (1990) 19-33]. In addition, the difference between DiC8 and the other protein kinase activators was also observed in the pattern of 86Rb efflux from preloaded glomerulosa cells; only DiC8 mimicked the effect of angiotensin II on ion fluxes. Furthermore, staurosporine, a potent inhibitor of protein kinase C, was capable of amplifying the aldosterone output induced by a maximally effective concentration of DiC8 or angiotensin II. These data suggest that the effect of the cell permeant DiC8 on aldosterone biosynthesis either is not mediated by protein kinase C activation, or is mediated by a phorbol ester-insensitive isoenzyme of protein kinase C.
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PMID:Contrasting effects of sn-1,2-dioctanoyl glycerol as compared to other protein kinase C activators in adrenal glomerulosa cells. 191 21

1. Mouse atria were incubated with [3H]-noradrenaline and the outflow of radioactivity induced by electrical field stimulation (5 Hz, 60 s) was used as an index of noradrenaline release. Angiotensin II (1 x 10(-8) M) significantly enhanced the stimulation-induced (S-I) outflow of radioactivity. 2. Phorbol 12-myristate 13-acetate (0.001-1.0 x 10(-6) M) and phorbol 12, 13-dibutyrate (0.001-1.0 x 10(-6) M), protein kinase C activating phorbol esters, significantly enhanced the S-I outflow of radioactivity. Phorbol dibutyrate produced a greater maximal enhancement of S-I outflow of radioactivity than phorbol myristate acetate. The enhancement of S-I outflow of radioactivity produced by the combination of phorbol dibutyrate (1.0 x 10(-7) M) and phorbol myristate acetate (1.0 x 10(-7) M) was no greater than that produced by phorbol dibutyrate (1.0 x 10(-7) M) alone. The enhancement of S-I outflow of radioactivity produced by phorbol myristate acetate (1.0 x 10(-7) M) was constant whether the tissue was exposed for 15, 45 or 75 min. 3. When angiotensin II (1.0 x 10(-8) M) was present with the maximally effective concentration of phorbol dibutyrate (1.0 x 10(-7) M) it did not increase S-I outflow of radioactivity. 8-bromo-cyclic AMP (9.0 x 10(-5) M) by itself increased the S-I outflow of radioactivity and in the presence of the maximally effective concentration of phorbol dibutyrate the enhancement of S-I outflow of radioactivity produced by 8-bromo-cyclic AMP was maintained. 4. A protein kinase inhibitor, K-252a (1.0 x 10(-6) M), did not affect S-I outflow of radioactivity. K-252a significantly reduced the enhancement of S-I outflow of radioactivity produced by both phorbol myristate acetate (0.03 or 0.1 x 10(-6) M) and phorbol dibutyrate (0.01 or 1.0 x 10(-6) M). 5. K-252a (1.0 x 10(-6) M) blocked the enhancement of S-I outflow of radioactivity produced by angiotensin II (1.0 x 10(-8) M) and tetraethylammonium (1.0 x 10(-4) M). 6. These results suggest that angiotensin II receptors may enhance noradrenaline release through the pool of protein kinase C that is activated by phorbol dibutyrate.
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PMID:Evidence that angiotensin II enhances noradrenaline release from sympathetic nerves in mouse atria by activating protein kinase C. 193 83

Previous studies have shown that vascular endothelial cells exhibit a highly active Na-K-Cl cotransport system that is regulated by a variety of vasoactive hormones and neurotransmitters, suggesting that the cotransporter may play an important role in endothelial cell function. In this study, the regulation of endothelial cell Na-K-Cl cotransport was further investigated by probing the stimulus-transfer pathway by which vasoactive agents stimulate the cotransporter. Specifically, three peptides previously shown to stimulate cotransport activity (angiotensin II, vasopressin, and bradykinin) were evaluated. Na-K-Cl cotransport was assessed in cultured bovine aortic endothelial cells as bumetanide-sensitive K+ influx. Stimulation of Na-K-Cl cotransport by angiotensin II, vasopressin, or bradykinin was found to be reduced either by removal of extracellular Ca2+ or by treatment of the cells with 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate or 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. In addition, the calmodulin antagonist W-7 was found to prevent stimulation of endothelial cell Na-K-Cl cotransport by the three peptides. These findings suggest that regulation of endothelial cell cotransport by these vasoactive peptides may be both Ca(2+)- and calmodulin-dependent. Angiotensin II, vasopressin, and bradykinin were also found to elevate phosphatidylinositol hydrolysis in the cultured endothelial cells. Thus, the possibility that regulation of endothelial Na-K-Cl cotransport by these vasoactive peptides also involves diacylglycerol activation of protein kinase C was investigated. A 10-min exposure of the endothelial cells to low doses of phorbol 12-myristate 13-acetate was found to reduce Na-K-Cl cotransport whether in the presence or absence of angiotensin II, vasopressin, or bradykinin. However, down-regulation of protein kinase C by a 40-h exposure to higher doses of the phorbol ester was found to elevate Na-K-Cl cotransport activity under both control and agonist-stimulated conditions, indicating that activation of protein kinase C results in inhibition of endothelial cell Na-K-Cl cotransport. Thus, protein kinase C activation may serve as negative feedback in the stimulus-transfer pathway by which these agonists regulate endothelial cell Na-K-Cl cotransport.
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PMID:Endothelial cell sodium-potassium-chloride cotransport. Evidence of regulation by Ca2+ and protein kinase C. 205 Jun 66

Endothelin (ET), a peptide originally isolated from the supernatants of cultured endothelial cells, exerts a wide variety of biological effects in different tissues. Endothelial-cell-synthesized ET-1 has been proposed to act in a paracrine manner on adjacent smooth muscle cells (SMC) in vivo, with effects that include both vascular reactivity (vasodilation/vasoconstriction) and mitogenesis. This study, by the use of immunocytochemically characterized SMC (rVSMC) isolated from the aortas of spontaneously hypertensive rats, has investigated a possible autocrine role for ET in regulation of the vasculature. Although quiescent cultures of rVSMC apparently did not constitutively express prepro ET-1mRNA, ET-specific transcripts could be induced by a variety of growth factors (transforming growth factor beta [TGF-beta]; platelet-derived growth factor-AA homodimer [PDGF-A chain]) and vasoactive hormones (angiotensin II [Ang II], arginine-vasopressin, and ET-1 itself). The kinetics for prepro ET-1mRNA induction in rVSMC were characteristically rapid in onset and transient. Down-regulation of protein kinase C by 48 h pretreatment of rVSMC with phorbol ester markedly reduced the subsequent ability of rVSMC to express ET-1 transcripts and secrete ET-1 peptide in response to Ang II. Inducible prepro ET-1mRNA expression was accompanied by a cycloheximide-inhibitable release of ET-1 peptide into the medium of rVSMC. ET-1 peptide was determined by both radioreceptor- and radioimmunoassay. Stimulated rVSMC accumulated ET-1 (approximately 200 pg.10(6) cells-1 x 4 h-1) at levels that attained biological relevance (approximately 10(-10) M). Sep-pak C18 extracts of medium from stimulated rVSMC elicited contraction of isolated endothelium-denuded rat mesenteric resistance vessels, and this response was characteristically protracted and difficult to "wash out." Synthetic (porcine) ET-1 promoted the expression of transcripts for PDGF-A chain, TGF-beta, and thrombospondin in quiescent rVSMC. Such effects of ET-1 on gene expression may be relevant to the mitogenic potential of ET-1 on VSMC. Our findings imply a role for ET-1 in the control of vascular function via both paracrine and autocrine regulatory mechanisms. The expression of prepro ET-1mRNA and peptide biosynthesis by rVSMC may have both short-term (e.g., vasoconstriction) and long-term (e.g., structural remodeling) consequences. A sustained loop of autocrine stimulation by ET-1 in SMC could contribute toward the pathogenesis of vasospasm and/or atherosclerosis.
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PMID:Stimulation of endothelin mRNA and secretion in rat vascular smooth muscle cells: a novel autocrine function. 207 71

We investigated the vascular responsiveness to vasoactive agents and the inhibition by H-7 (1-(5-isoquinoline-sulfonyl)-2-methylpiperazine), which inhibits cyclic nucleotide-dependent protein kinases and protein kinase C(PKC) equally potently in helically cut strips of thoracic aortas from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). The susceptibility of norepinephrine (NE)- and angiotensin II (Ang II)-induced contractions to H-7 was significantly higher in the aortas from SHR than in those from WKY. H-7 decreased the contractile responses to KCl to a similar extent in both strains without affecting the high K(+)-stimulated Ca2+ influx. H-7 produced a shift to the right of the dose-response curve for the PKC activator, 12-o-tetradecanoylphorbol-13-acetate (TPA) in the case of SHR aortas, while no such shift was noted in tissues from WKY. Functional alterations in the PKC branch of the Ca2+ messenger system in vascular smooth muscle may play an important role in SHR during the sustained contraction.
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PMID:Effects of H-7 (protein kinase inhibitor) and phorbol ester on aortic strips from spontaneously hypertensive rats. 210 66


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