scholarly journals Possible bi-directional link between ETAreceptors and protein kinase C in rat blood vessels

1995 ◽  
Vol 4 (1) ◽  
pp. 55-59 ◽  
Author(s):  
A. M. Northover ◽  
B. J. Northover
Keyword(s):  
Small Intestine ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Blood Vessels ◽  
Mesenteric Artery ◽  
Perfusion Pressure ◽  
Pkc Inhibitor ◽  
Kinase C ◽  
Before And After ◽  
Pre Treatment

Possible links have been investigated between activation of protein kinase C (PKC) and endothelin (ET) production by small blood vessels. Perfusion pressures were recorded from rat isolated mesenteric artery, with or without the small intestine attached, before and after addition to the perfusate of either ET-1, ET-3 or the PKC activator 12-deoxyphorbol 13-phenylacetate (DOPPA). Rises in perfusion pressure in response to ET-1 (10−8M)or DOPPA (10−6M) were reduced significantly by pre-treatment with either the ETAreceptor antagonist PD151242 (10−6M) or the PKC inhibitor Ro 31-8220 (10−6M). ET-3 (10−8M) had a significant, albeit small, effect only when the gut was still attached to the mesentery. Inthis latter preparation ET-1 and DOPPA increased the permeability of villi microvessels to colloidal carbon in the perfusate. This effect of DOPPA was reduced by pre-treatment with either PD151242 or Ro 31-8220, but the effects of ET-1 were reduced significantly only by Ro 31-8220. ET-3 (10−8M) was without effect. The results suggest a possible bi-directional link between ETAreceptors and PKC in the intestinal vasculature.

Dexamethasone decreases neuronal nitric oxide release in mesenteric arteries from hypertensive rats through decreased protein kinase C activation

2009 ◽  
Vol 117 (8) ◽  
pp. 305-312 ◽  
Author(s):  
Rosa Aras-López ◽  
Fabiano E. Xavier ◽  
Mercedes Ferrer ◽  
Gloria Balfagón
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Glucocorticoid Receptors ◽  
Electrical Field Stimulation ◽  
Mesenteric Arteries ◽  
Hypertensive Rats ◽  
Pkc Inhibitor ◽  
Kinase C ◽  
No Release ◽  
Wistar Kyoto

Neuronal NO plays a functional role in many vascular tissues, including MAs (mesenteric arteries). Glucocorticoids alter NO release from endothelium and the CNS (central nervous system), but no results from peripheral innervation have been reported. In the present study we investigated the effects of dexamethasone on EFS (electrical field stimulation)-induced NO release in MAs from WKY (Wistar–Kyoto) rats and SHRs (spontaneously hypertensive rats) and the role of PKC (protein kinase C) in this response. In endothelium-denuded MAs, L-NAME (NG-nitro-L-arginine methyl ester) increased the contractile response to EFS only in segments from SHRs. EFS-induced contraction was reduced by 1 μmol/l dexamethasone in segments from SHRs, but not WKY rats, and this effect was abolished in the presence of dexamethasone. EFS induced a tetrodotoxin-resistant NO release in WKY rat MAs, which remained unchanged by 1 μmol/l dexamethasone. In SHR MAs, dexamethasone decreased basal and EFS-induced neuronal NO release, and this decrease was prevented by the glucocorticoid receptor antagonist mifepristone. Dexamethasone did not affect nNOS [neuronal NOS (NO synthase)] expression in either strain. In SHR MAs, incubation with calphostin C (a non-selective PKC inhibitor), Gö6983 (a classic PKC δ and ζ inhibitor), LY379196 (a PKCβ inhibitor) or PKCζ-PI (PKCζ pseudosubstrate inhibitor) decreased both basal and EFS-induced neuronal NO release. Additionally, PKC activity was reduced by dexamethasone. The PKC inhibitor-induced reduction in NO release was unaffected by dexamethasone. In conclusion, results obtained in the present study indicate that PKC activity positively modulates the neuronal NO release in MAs from SHRs. They also reveal that by PKC inhibition, through activation of glucocorticoid receptors, dexamethasone reduces neuronal NO release in these arteries.

Relaxin stimulates atrial natriuretic peptide secretion in perfused rat heart

1996 ◽  
Vol 150 (3) ◽  
pp. 487-495 ◽  
Author(s):  
M Toth ◽  
P Taskinen ◽  
H Ruskoaho
Keyword(s):  
Heart Rate ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Rat Heart ◽  
Perfusion Pressure ◽  
Kinase Inhibitor ◽  
Dependent Protein Kinase ◽  
Kinase C ◽  
Dependent Protein ◽  
Heart Preparation

Abstract Relaxin, a reproductive hormone of the insulin-like growth factor family, increases heart rate in experimental animals but its other actions on cardiac function and cellular mechanisms responsible for the positive chronotrophic effect remain unknown. We have studied the actions of human recombinant gene-2 relaxin on the release of atrial natriuretic peptide (ANP) and cardiac function (heart rate, contractile force, perfusion pressure) as well as the underlying signal transduction mechanisms by using the isolated perfused spontaneously beating rat heart preparation. The administration of relaxin into the perfusion fluid at concentrations of 1·5, 3 or 10 nm for 30 min caused a dose-dependent sustained increase in heart rate, while contractile force and perfusion pressure remained unchanged. In addition, infusion of relaxin at a concentration of 10 nm into the perfusate produced a gradual 1·5-fold increase in immunoreactive ANP (IR-ANP) secretion (from 456 ± 76 to 701 ± 124 pg/ml, F=4·5, P<0·001). The ANP secretory and chronotrophic effects of relaxin appear to involve the activation of protein kinase C, since administration of a protein kinase C inhibitor staurosporine at a concentration of 30 nm completely blocked the effect of relaxin (10 nm) on IR-ANP secretion P<0·001) and heart rate (P<0·001). A cAMP-dependent protein kinase inhibitor, H-89 (100 nm), also substantially reduced the ANP secretory effect of relaxin and attenuated the increase in heart rate during the sustained phase of the relaxin infusion (P<0·001). KN-62 (3 μm), a Ca2+/calmodulin-dependent protein kinase inhibitor, decreased the positive chronotrophic effect of relaxin (P<0·001) but did not influence significantly the effect of relaxin on IR-ANP release in isolated perfused rat heart preparation. These results provide the first evidence that relaxin stimulates the secretion of ANP from isolated perfused rat hearts. Our results also suggest that relaxin modulates ANP secretion by activation of protein kinase C and cAMP-dependent protein kinase pathways. Journal of Endocrinology (1996) 150, 487–495

The PKC- Inhibitor Enzastaurin Inhibits MM Cell Growth, Survival and Migration in the Bone Marrow Microenvironment.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1584-1584 ◽  
Author(s):  
Klaus Podar ◽  
Marc S. Raab ◽  
Dean Abtahi ◽  
Yu-Tzu Tai ◽  
Boris Lin ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase C ◽  
Cell Migration ◽  
Protein Kinase ◽  
Cell Growth ◽  
Cell Lines ◽  
Pkc Inhibitor ◽  
Kinase C ◽  
Pkc Signaling ◽  
And Migration

Abstract Members of the protein kinase C (PKC) family of serine- threonine protein kinases mediate multiple physiological functions including differentiation, growth and survival, invasiveness, angiogenesis and drug efflux. Dysregulation of PKC signaling has been implicated in tumor progression and prompted the development of novel anticancer therapeutics. In multiple myeloma (MM) PKC isoforms are: (1) involved in MM cell apoptosis; (2) associated with VEGF- and Wnt- induced MM cell migration; and (3) controlling shedding of IL-6 receptor alpha. However, to date the potential of targeting PKC signaling sequelae in MM has not been evaluated. Here we investigated the novel orally available protein- kinase C (PKC) inhibitor Enzastaurin (Eli Lilly and Company) for its therapeutic efficacy in MM. We first tested the ability of Enzastaurin to suppress MM cell proliferation in a wide array of MM cell lines. Our data show that Enzastaurin inhibits 3H[dT] uptake in all cell lines tested in a low micromolar range equivalent to the concentration range achieved in the patient plasma during clinical trials. Importantly, Enzastaurin also abrogates MM cell proliferation in a BMSC-MM coculture system. We next sought to determine whether Enzastaurin can inhibit cell survival and found dose- dependent induction of MM cell apoptosis in MM cell lines MM.1S, MM.1R, OPM-1, OPM-2, RPMI-8226, and RPMI-dox40. Moreover, Enzastaurin significantly inhibited VEGF- induced MM cell migration on fibronectin. Importantly, IGF-1- induced MM cell migration was abrogated by Enzastaurin, demonstrating the requirement of PKC. Signaling pathways mediating these effects were next examined: Our data show that Enzastaurin abrogates phosphorylation of Akt and GSK3beta, which is required for MM cell growth and migration. Furthermore, ongoing studies are evaluating the efficacy of Enzastaurin in a murine model of human MM. Taken together, these studies show for the first time the preclinical efficacy of the orally available PKC inhibitor Enzastaurin providing the basis for its clinical evaluation to improve patient outcome in MM.

scholarly journals CalDAG-GEFI and protein kinase C represent alternative pathways leading to activation of integrin αIIbβ3 in platelets

Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 1696-1703 ◽  
Author(s):  
Stephen M. Cifuni ◽  
Denisa D. Wagner ◽  
Wolfgang Bergmeier
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Small Gtpase ◽  
Wild Type ◽  
Pkc Inhibitor ◽  
Integrin Αiibβ3 ◽  
Alternative Pathways ◽  
Kinase C ◽  
Induced Aggregation ◽  
Inside Out

AbstractSecond messenger-mediated inside-out activation of integrin αIIbβ3 is a key step in platelet aggregation. We recently showed strongly impaired but not absent αIIbβ3-mediated aggregation of CalDAG-GEFI–deficient platelets activated with various agonists. Here we further evaluated the roles of CalDAG-GEFI and protein kinase C (PKC) for αIIbβ3 activation in platelets activated with a PAR4 receptor–specific agonist, GYPGKF (PAR4p). Compared with wild-type controls, platelets treated with the PKC inhibitor Ro31-8220 or CalDAG-GEFI–deficient platelets showed a marked defect in aggregation at low (< 1mM PAR4p) but not high PAR4p concentrations. Blocking of PKC function in CalDAG-GEFI–deficient platelets, how-ever, strongly decreased aggregation at all PAR4p concentrations, demonstrating that CalDAG-GEFI and PKC represent separate, but synergizing, pathways important for αIIbβ3 activation. PAR4p-induced aggregation in the absence of CalDAG-GEFI required cosignaling through the Gαi-coupled receptor for ADP, P2Y12. Independent roles for CalDAG-GEFI and PKC/Gαi signaling were also observed for PAR4p-induced activation of the small GTPase Rap1, with CalDAG-GEFI mediating the rapid but reversible activation of this small GTPase. In summary, our study identifies CalDAG-GEFI and PKC as independent pathways leading to Rap1 and αIIbβ3 activation in mouse platelets activated through the PAR4 receptor.

Effect of protein kinase C inhibitors on endothelin- and vasopressin-induced constriction of the rat basilar artery

1992 ◽  
Vol 263 (6) ◽  
pp. H1643-H1649 ◽  
Author(s):  
M. A. Murray ◽  
F. M. Faraci ◽  
D. D. Heistad
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Basilar Artery ◽  
Arginine Vasopressin ◽  
Vessel Diameter ◽  
Pkc Inhibitor ◽  
Cranial Window ◽  
Kinase C ◽  
Basilar Arteries

The goal of this study was to determine whether inhibitors of protein kinase C (PKC) attenuate constrictor responses of the basilar artery in vivo to endothelin and arginine vasopressin. In anesthetized rats, the diameter of basilar arteries was measured through a cranial window [control diameter 218 +/- 3 (SE) microns]. Vessel diameter was measured during topical application of agonists and antagonists. Sphingosine (10(-6) M), a PKC inhibitor that binds to the regulatory site of PKC, attenuated vasoconstriction in response to endothelin (10(-9), 10(-8), and 10(-7) M) and vasopressin (10(-9) and 10(-8) M). H-7 (10(-9) M), a PKC inhibitor that binds to the catalytic site of PKC, also inhibited vasoconstriction in response to endothelin and vasopressin. Sphingosine and H-7 did not affect baseline diameter and did not attenuate vasoconstriction in response to prostaglandin (PG) F2 alpha. The V1 antagonist [d(CH2)5Tyr(Me)]arginine vasopressin (10(-8) M) significantly inhibited constriction in response to vasopressin (10(-9) and 10(-8) M) but not PGF2 alpha (10(-6) M). These observations suggest that activation of PKC may contribute to endothelin-induced constriction of the basilar artery in vivo and that PKC may also be a mediator of V1-receptor-mediated constriction of the basilar artery in response to vasopressin.

scholarly journals Regulation of phospholipase D by sphingosine involves both protein kinase C-dependent and -independent mechanisms in NIH 3T3 fibroblasts

1992 ◽  
Vol 288 (3) ◽  
pp. 853-858 ◽  
Author(s):  
Z Kiss ◽  
E Deli
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phospholipase D ◽  
Activity Data ◽  
Pkc Inhibitor ◽  
Phospholipid Hydrolysis ◽  
3T3 Fibroblasts ◽  
Kinase C ◽  
Nih 3T3 ◽  
Hydrolysis Of

Previously, the protein kinase C (PKC) inhibitor sphingosine was found to stimulate phospholipase D (PLD)-mediated hydrolysis of both phosphatidylethanolamine (PtdEtn) and phosphatidylcholine (PtdCho) in NIH 3T3 fibroblasts [Kiss & Anderson (1990) J. Biol. Chem. 265, 7345-7350]. Here we examined the possible relationship between the opposite effects of sphingosine on PKC-mediated protein phosphorylation and PLD activation. After treatments for 3-5 min, sphingosine (25 microM) and the PKC activators phorbol 12-myristate 13-acetate (PMA) (100 nM), bryostatin (100 nM) or platelet-derived growth factor (50 ng/ml) synergistically stimulated the hydrolysis of both PtdEtn and PtdCho in NIH 3T3 fibroblasts prelabelled with [14C]ethanolamine or [14C]choline. Inhibition of PMA-induced phospholipid hydrolysis could also be elicited by sphingosine, but this process required prolonged (60 min) treatments of fibroblasts with 40-60 microM-sphingosine. Similarly to sphingosine, the protein phosphatase inhibitor okadaic acid also had either potentiating or inhibitory effects on PMA-stimulated PLD activity, depending on the length of incubation time and the concentration of PMA. Consistent with the presence of an inhibitory component in the overall action of PKC, the PKC inhibitor staurosporine and down-regulation of PKC activity by prolonged (24 h) treatment with PMA similarly enhanced PLD activity. Data suggest that (a) sphingosine may enhance PMA-mediated phospholipid hydrolysis by neutralizing the action of an inhibitory PKC isoform, and that (b) the stimulatory PKC isoform is less sensitive to the inhibitory action of sphingosine.

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