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)

To assess the role of protein kinase C (PKC) in the control of vessel tone in vivo in genetic hypertension, the vascular effects of phorbol-12,13-dibutyrate (PDBu), a PKC activator, was measured in the autoperfused hindlimb of reserpinized spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). PDBu infusion (1-3000 ng/kg/min) into the hindlimb elevated perfusion pressure in a dose-related manner. Vasoconstriction response characteristics (latency, T1/2 to peak effect, decay of effect) of PDBu were significantly longer (2- to 10-fold) than that produced by membrane receptor agonists; phenylephrine, SKF 89748, a lipophilic alpha-1 agonist, angiotensin II and 5-hydroxytryptamine. The tonic vasoconstriction induced by PDBu was not antagonized by prazosin, rauwolscine, cyproheptadine, [Sar1lle8]-angiotensin II but was inhibited reversibly by microbial PKC-inhibitors, K252a and staurosporine at concentrations (1.56-2.8 micrograms/kg/min) which did not block vasoconstriction by phenylephrine or 5-hydroxytryptamine. The EC50 for PDBu was identical in SHR and WKY. However, the maximal response to PDBu was significantly greater in SHR compared to WKY. Staurosporine lowered mean arterial pressure equally in SHR (20%) and WKY (17%) but reduced perfusion pressure in SHR (13%) to a slightly greater extent than in WKY (5%). Unlike the in vivo response, aortic rings removed from SHR were more sensitive to cumulative doses of PDBu than rings from WKY. It is concluded that PDBu-vasoconstriction in vivo is mediated largely through activation of PKC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phorbol-12,13-dibutyrate-induced vasoconstriction in vivo: characterization of response in genetic hypertension. 231 87

Considerable controversy exists concerning the possible role of lead in the etiology of human hypertension. In animal studies, there is convincing evidence that lead alters cardiovascular responsiveness; rats drinking water containing 100 ppm lead develop a chronic, significant 15 to 20 mm Hg elevation in systolic blood pressure. Pressor responsiveness to catecholamines is enhanced in animals chronically exposed to lead, and the responsiveness of isolated vascular smooth muscle to adrenergic agonists is increased in rats with lead-induced hypertension. Experimental evidence suggests that alterations in the cellular mechanisms that regulate intracellular calcium concentration may contribute to the abnormal vascular function in lead-induced hypertension. Recent work in our laboratory indicates that increased vascular reactivity in genetic hypertension is associated with altered activity of the protein kinase C branch of the calcium messenger system. Contractile responses to lead in rabbit mesenteric artery are potentiated by activators (phorbol esters) of this enzyme complex, and a selective inhibitor of protein kinase C inhibited contractions induced by lead. Based on these results, it is proposed that a cellular component of the action of lead to increase vascular reactivity may relate to the role of protein kinase C in smooth muscle contraction.
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PMID:Effects of lead on vascular reactivity. 306 Mar 55

The mechanisms responsible for altered vascular smooth muscle cell (VSMC) function in hypertension remain unknown. In the spontaneously hypertensive rat (SHR) model of genetic hypertension, there are multiple abnormalities in VSMC function, including increased growth, Na(+)-H+ exchange, and increased signal transduction by protein kinase C. The family of kinases termed mitogen-activated protein (MAP) kinases has recently been shown to be essential mediators of growth factor signal transduction. In the present study, alterations in MAP kinase function in the hypertensive phenotype were investigated using early-passage SHR and Wistar-Kyoto (WKY) VSMCs stimulated with angiotensin II (Ang II, 100 nmol/L) or platelet-derived growth factor-BB (PDGF-BB, 10 ng/mL). MAP kinase activity was measured by in-gel kinase assays and Western blot analysis. Two differences between SHR and WKY rats were observed for Ang II-mediated MAP kinase activation: (1) Inactivation after Ang II stimulation was more rapid in SHR than WKY VSMCs. (2) Activity in SHR VSMCs showed a greater dependence on Ca2+ mobilization, since chelation of intracellular Ca2+ with BAPTA inhibited maximal activity by 95% in SHR VSMCs but by only 50% in WKY VSMCs. In contrast to the results with Ang II, no differences in PDGF-stimulated MAP kinase activity were observed. These findings establish activation of MAP kinase by Ang II as a feature that distinguishes SHR VSMCs from WKY VSMCs and suggest that differences in regulation of MAP kinase signaling may alter cellular events that are increased in the SHR genetic model of hypertension.
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PMID:Ca(2+)-dependent mitogen-activated protein kinase activation in spontaneously hypertensive rat vascular smooth muscle defines a hypertensive signal transduction phenotype. 863 46

The objectives of the present study were to determine whether angiotensin II (Ang II) modifies beta-adrenoceptor-induced cAMP production in preglomerular microvascular smooth muscle cells (PMVSMCs), to determine whether the Ang II/beta-adrenoceptor interaction on cAMP production differs in PMVSMCs from normotensive Wistar-Kyoto (WKY) rats vs. PMVSMCs from spontaneously hypertensive rats (SHR), and to elucidate the mechanism of Ang II/beta-adrenoceptor interactions on cAMP production in PMVSMCs. In cultured PMVSMCs, isoproterenol increased cAMP levels and this effect was markedly enhanced by Ang II. The Ang II enhancement of isoproterenol-induced cAMP was significantly greater in SHR PMVSMCs compared with WKY PMVSMCs. Neither inhibition of calcineurin with FK506, inhibition of calcium-calmodulin with W-7 and calmidazolium, nor inhibition of Gi proteins with pertussis toxin attenuated Ang II enhancement of isoproterenol-induced cAMP in PMVSMCs from either SHR or WKY rats. Moreover, the effect of Ang II on isoproterenol-induced cAMP was not mimicked by alpha-2 adrenoceptor stimulation. In contrast, chelation of intracellular calcium with BAPTA-AM attenuated, increasing intracellular calcium with A23187 augmented, and inhibition of protein kinase C with either calphostin C or chelerythrine chloride abolished Ang II enhancement of isoproterenol-induced cAMP. We conclude that in cultured PMVSMCs Ang II enhances the cAMP response to beta-adrenoceptor agonists via a mechanism that involves coincident activation of adenylyl cyclase by stimulatory G proteins and protein kinase C. Thus, protein kinase C-mediated activation of adenylyl cyclase may attenuate Ang II-induced vasoconstriction in the renal microcirculation by raising the intracellular levels of cAMP, and this mechanism may be augmented in genetic hypertension.
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PMID:Modulation by angiotensin II of isoproterenol-induced cAMP production in preglomerular microvascular smooth muscle cells from normotensive and genetically hypertensive rats. 976 41

Angiotensin II (Ang II)-induced phospholipase D (PLD) activity is greater in aortic smooth muscle from spontaneously hypertensive rats (SHR) versus normotensive Wistar-Kyoto rats (WKY). Whether and how this signaling pathway is altered in preglomerular microvascular smooth muscle cells (PGSMCs), a cell type that may participate in genetic hypertension, is unknown. The goals of the present study were to determine in SHR and WKY PGSMCs the following: (1) whether Ang II induces PLD activity; (2) whether the effect of Ang II on PLD activity is greater in SHR; (3) which PLD isoform is stimulated by Ang II; (4) what signaling pathway mediates Ang II-induced PLD stimulation; and (5) whether the signaling pathways mediating Ang II-induced PLD activity are different in SHR and WKY. The EC(50) for Ang II-induced PLD stimulation in SHR was 10-fold lower than the EC(50) in WKY, and both were inhibited by L-158,805, an AT(1) antagonist. Inhibitors of phosphoinositol-3-kinase and protein kinase C did not block Ang II-induced PLD activity in SHR and WKY PGSMCs. Catalytically-inactive constructs of PLD2 and RhoA, but not PLD1, ADP ribosylation factor 1 (ARF1), ARF6, or ADP ribosylation factor nucleotide exchange factor (ARNO) blocked Ang II-induced PLD activity in SHR and WKY PGSMCs. Brefeldin A completely blocked Ang II-induced PLD activity in SHR but only slightly reduced Ang II-induced PLD activity in WKY PGSMCs. Therefore, we conclude that in PGSMCs, the effect of Ang II on PLD activity is (1) greater in SHR; (2) mediated by AT(1) receptors signaling to PLD2; (3) transduced primarily by Rho proteins; and (4) inhibited in SHR by brefeldin A.
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PMID:Angiotensin II signaling to phospholipase D in renal microvascular smooth muscle cells in SHR. 1123 Mar 48

We have previously demonstrated that pressure application of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) onto some neurons in the anterior hypothalamic area of rats increases neural activity in vivo and that this PKC activation-induced increase of neural activity is enhanced in spontaneously hypertensive rats (SHR), an animal model for genetic hypertension. Activation of PKC increases expression of the c-fos gene, an important transcription factor and proto-oncogene thought to be a marker of neural activity. To evaluate PKC isoforms responsible for neural activation, we examined which isoforms of PKC are involved in the PKC activation-induced c-fos gene expression in neuronal cultures of Wistar rat and spontaneously hypertensive rat (SHR) brains. PMA increased c-fos gene expression in neuronal cultures of Wistar rat brain and the PMA-induced c-fos gene expression was inhibited by the PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7). The PKCalpha,beta,gamma activator thymeleatoxin also increased c-fos gene expression, while the PKCdelta,epsilon activator ingenol did not affect it. In addition, the PMA-induced c-fos gene expression was inhibited by PKCbetaantisense oligonucleotides (AON) but not by PKCalpha and PKCgammaAONs. In SHR brain neuronal cultures, the PMA-induced c-fos gene expression was enhanced as compared with that of Wistar Kyoto rats (WKY), while basal c-fos gene expression was almost the same in both neuronal cultures. The enhancement of PMA-induced c-fos gene expression in SHR brain cultures was abolished by PKCbetaAON. These findings suggest that in rat brain neuronal cultures, PMA increases c-fos gene expression via activation of PKC and that PKCbetaisoforms are partly involved in the PMA-induced c-fos gene expression. In neuronal cultures of SHR brain, it appears that the PMA-induced c-fos gene expression is also enhanced via PKCbeta.
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PMID:Role of protein kinase C beta in phorbol ester-induced c-fos gene expression in neurons of normotensive and spontaneously hypertensive rat brains. 1580 34

Cardiac sympathetic nerves release neuropeptide Y (NPY)1-36, and peptide YY (PYY)1-36 is a circulating peptide; therefore, these PP-fold peptides could affect cardiac fibroblasts (CFs). We examined the effects of NPY1-36 and PYY1-36 on the proliferation of and collagen production ([(3)H]proline incorporation) by CFs isolated from Wistar-Kyoto (WKY) normotensive rats and spontaneously hypertensive rats (SHRs). Experiments were performed with and without sitagliptin, an inhibitor of dipeptidyl peptidase 4 [DPP4; an ectoenzyme that metabolizes NPY1-36 and PYY1-36 (Y1 receptor agonists) to NPY3-36 and PYY3-36 (inactive at Y1 receptors), respectively]. NPY1-36 and PYY1-36, but not NPY3-36 or PYY3-36, stimulated proliferation of CFs, and these effects were more potent than ANG II, enhanced by sitagliptin, blocked by BIBP3226 (Y1 receptor antagonist), and greater in SHR CFs. SHR CF membranes expressed more receptor for activated C kinase (RACK)1 [which scaffolds the Gi/phospholipase C (PLC)/PKC pathway] compared with WKY CF membranes. RACK1 knockdown (short hairpin RNA) and inhibition of Gi (pertussis toxin), PLC (U73122), and PKC (GF109203X) blocked the proliferative effects of NPY1-36. NPY1-36 and PYY1-36 stimulated collagen production more potently than did ANG II, and this was enhanced by sitagliptin and greater in SHR CFs. In conclusion, 1) NPY1-36 and PYY1-36, via the Y1 receptor/Gi/PLC/PKC pathway, activate CFs, and this pathway is enhanced in SHR CFs due to increased localization of RACK1 in membranes; and 2) DPP4 inhibition enhances the effects of NPY1-36 and PYY1-36 on CFs, likely by inhibiting the metabolism of NPY1-36 and PYY1-36. The implications are that endogenous NPY1-36 and PYY1-36 could adversely affect cardiac structure/function by activating CFs, and this may be exacerbated in genetic hypertension and by DPP4 inhibitors.
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PMID:NPY1-36 and PYY1-36 activate cardiac fibroblasts: an effect enhanced by genetic hypertension and inhibition of dipeptidyl peptidase 4. 2637 Nov 60