Cicletanine reverses vasoconstriction induced by the endogenous sodium pump ligand, marinobufagenin, via a protein kinase C dependent mechanism

Bagrov, Alexei Y.; Dmitrieva, Renata I.; Дорофеева, Н. А.; Федорова, О. В.; Lopatin, Denis A.; Lakatta, Edward G.; Droy-Lefaix, Marie-Thérèse

doi:10.1097/00004872-200018020-00012

Cited by 15 publications

(13 citation statements)

References 33 publications

(34 reference statements)

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“…Our recent results, indeed, demonstrate that the vasodilatory effect of cicletanine is PKC dependent in human mesenteric arteries precontracted with MBG. 11 In the present study, cicletanine treatment of DS was associated with an improvement of renal function. Previous studies also documented that cicletanine, even at subdepressor doses, exhibited renal-protective effects.…”

Section: Discussionsupporting

confidence: 58%

“…Recently, we have demonstrated that, indeed, cicletanine does reverse the MBG-induced vasoconstriction and NKA inhibition by way of a PKC-sensitive mechanism. 11 This effect of cicletanine was blocked by phorbol ester and was, therefore, modulated by phorbolsensitive PKC isoforms, such as ␤2 and ␦. Our present results show that although in vivo cicletanine treatment did not affect the increased expression of ␣-1 NKA protein in the myocardium effected by the high-NaCl diet, it reduced the sensitivity of LV sarcolemmal NKA to MBG and prevented the reduction in sarcolemmal NKA activity.…”

Section: Discussionmentioning

confidence: 99%

“…10 Recently, we have demonstrated that cicletanine, a furopyridine antihypertensive compound with natriuretic and vasorelaxant actions, directly inhibits PKC activity and antagonizes the vasoconstrictor and NKA-inhibitory effects of MBG by a PKC-sensitive mechanism. 11 Phorbol diacetate, which stimulates PKC, reversed the effect of cicletanine on MBG-induced NKA inhibition and vasoconstriction. 11 Thus, it appears that both SPLs and PKC may modulate NKA activity in cardiovascular tissues.…”

mentioning

confidence: 95%

“…11 Phorbol diacetate, which stimulates PKC, reversed the effect of cicletanine on MBG-induced NKA inhibition and vasoconstriction. 11 Thus, it appears that both SPLs and PKC may modulate NKA activity in cardiovascular tissues. Because hypertension is known to be associated with activation of PKC in left ventricular (LV) myocardium, 12,13 it is possible that enhanced phosphorylation of ␣-1 NKA could sensitize the LV sodium pumps to MBG.…”

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confidence: 99%

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Myocardial PKC β2 and the Sensitivity of Na/K-ATPase to Marinobufagenin Are Reduced by Cicletanine in Dahl Hypertension

et al. 2003

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Abstract-Marinobufagenin (MBG), an endogenous ligand of ␣-1 Na/K-ATPase, becomes elevated and contributes to hypertension in NaCl-loaded Dahl-S rats (DS). Protein kinase C (PKC) phosphorylates ␣-1 Na/K-ATPase and increases its MBG sensitivity. Cicletanine, an antihypertensive compound with PKC-inhibitory activity, reverses MBG-induced Na/K-ATPase inhibition and vasoconstriction. We hypothesized that increased PKC levels in sodium-loaded hypertensive DS would sensitize ␣-1 Na/K-ATPase to MBG and that PKC inhibition by cicletanine would produce an opposite effect. We studied the effects of cicletanine on systolic blood pressure, left ventricular PKC isoforms, cardiac ␣-1 Na/K-ATPase levels, and sensitivity to MBG in hypertensive DS. Seven DS received 50 mg · kg Ϫ1 · d Ϫ1 cicletanine, and 7 DS received vehicle during 4 weeks of an 8% NaCl diet. Vehicle-treated rats exhibited an increase in blood pressure, left ventricular mass, MBG excretion (74Ϯ11 vs 9Ϯ1 pmol/24 h, PϽ0.01), myocardial ␣-1 Na/K-ATPase protein, and PKC ␤2 and ␦. The sensitivity of Na/K-ATPase to MBG was enhanced at the level of high-affinity binding sites (IC 50 , 0.8 vs 4.4 nmol/L, PϽ0.01). Cicletanine-treated rats exhibited a 56-mm Hg reduction in blood pressure (PϽ0.01) and a 30% reduction in left ventricular weight, whereas cardiac ␣-1 Na/K-ATPase protein and MBG levels were unchanged. In cicletanine-treated rats, PKC ␤2 was not increased, the sensitivity of Na/K-ATPase to MBG was decreased (IC 50 ϭ20 mol/L), and phorbol diacetate-induced ␣-1 Na/K-ATPase phosphorylation was reduced versus vehicle-treated rats. In vitro cicletanine treatment of sarcolemma from vehicle-treated rats also desensitized Na/K-ATPase to MBG, indicating that this effect was not solely attributable to a reduction in blood pressure. Thus, PKC-induced phosphorylation of cardiac ␣-1 Na/K-ATPase is a likely target for cicletanine treatment. Key Words: rats, Dahl Ⅲ Na/K-transporting ATPase Ⅲ digitalis-like factor Ⅲ bufanolides Ⅲ hypertrophy Ⅲ protein kinases Ⅲ antihypertensive agents E ndogenous digitalis-like sodium pump ligands (SPLs) increase during states of NaCl retention to induce inhibition of the renal tubular sodium pump and natriuresis. 1,2 Enhanced SPL levels, however, can also inhibit Na/KATPase (NKA) in cardiovascular tissues and raise arterial pressure. 2,3 Recently, we have shown that plasma and urine levels of marinobufagenin (MBG), an endogenous bufadienolide NKA inhibitor, rather than endogenous ouabain, increases and contributes to hypertension in Dahl salt-sensitive rats (DS) maintained on a long-term high-NaCl intake. 4,5 In vitro, MBG acts as a vasoconstrictor 6,7 and exhibits selectivity toward ␣-1 isoform of the sodium pump, ie, the major isoform in renal tubules and adult cardiomyocytes. 4,6 Protein kinase C (PKC) can affect NKA activity by altering its phosphorylation state. 8,9 This modulatory effect of PKC is specific to the NKA ␣-1 isoform. 9,10 In arterial sarcolemma, PKC induces the phosphorylation of ␣-1 NKA and enhances the NKA sensitivity to M...

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 95%

mentioning

confidence: 99%

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Myocardial PKC β2 and the Sensitivity of Na/K-ATPase to Marinobufagenin Are Reduced by Cicletanine in Dahl Hypertension

et al. 2003

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“…31 This vasorelaxant effect of cicletanine did not occur in the presence of PDA. Thus, taken together, our present and previous results suggest that PKC activation potentiates, whereas PKC inhibition reverses both the NKA inhibitory and vasoconstrictor effects of MBG, and that PKC phosphorylation of the ␣ 1 -subunit of the sodium pump, at least in part, underlies this phenomenon.…”

Section: Discussionmentioning

confidence: 89%

Phorbol Diacetate Potentiates Na ⁺ -K ⁺ ATPase Inhibition by a Putative Endogenous Ligand, Marinobufagenin

et al. 2002

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Abstract-Several vasoconstrictor agents can regulate the phosphorylation status of the Na ϩ -K ϩ ATPase (NKA). We have recently demonstrated that mammalian tissues contain an endogenous bufadienolide, digitalis-like ␣ 1 -NKA-selective ligand, marinobufagenin (MBG). Protein kinase C induces phosphorylation of the ␣ 1 -NKA isoform, the major isoform in vascular smooth muscle, kidney, and heart cells. We hypothesized that protein kinase C-induced phosphorylation of NKA can potentiate the effect of endogenous digitalis-like ligands, and that such potentiation can occur in an NKA isoform-specific fashion. A protein kinase C activator, phorbol 12,13-diacetate (PDA, 50 nmol/L), induced phosphorylation of the ␣ 1 -NKA from human mesenteric artery (HMA) sarcolemma and rat kidney but not that of the ␣ 3 -NKA from rat fetal brain. In HMA sarcolemma, which predominantly contains ␣ 1 -NKA, PDA (50 nmol/L) potentiated the NKA-inhibitory effect of MBG at the level of high-affinity binding sites (0.05Ϯ0.03 nmol/L versus 4.0Ϯ1.7 nmol/L, PϽ0.05). In contrast, PDA did not affect the NKA inhibition by ouabain, an ␣ 3 -NKA ligand. In isolated endothelium-denuded HMA artery rings, 50 nmol/L PDA potentiated the MBG-induced vasoconstriction (EC 50 , 17Ϯ6 nmol/L versus 150Ϯ40 nmol/L; PϽ0.01). Our results suggest that ␣ 1 -isoform-specific NKA inhibition by the endogenous digitalis-like ligand, MBG, is substantially enhanced via NKA phosphorylation by protein kinase C. Thus, an interaction of protein kinase C-dependent phosphorylation and MBG on NKA activity may underlie the synergistic vasoactive effects of MBG and other endogenous vasoconstrictors in hypertension. Key Words: drug therapy Ⅲ ouabain Ⅲ Na ϩ -K ϩ -exchanging ATPase Ⅲ vasoconstriction Ⅲ protein kinases Ⅲ blood pressure Ⅲ bufanolides V arious vasorelaxants and vasoconstrictors can regulate vascular Na ϩ -K ϩ ATPase (NKA) activity via its phosphorylation/dephosphorylation by protein kinases and phosphatases. 1-3 Protein kinases phosphorylate the sodium pump in a tissue-and isoform-specific fashion. 4,5 Protein kinase C (PKC) directly phosphorylates the ␣ 1 -NKA isoform. 6,7 Several endogenous digitalis-like NKA inhibitors exist in mammalian plasma. 8 A cardenolide, a ouabain-like compound, was the first endogenous sodium pump inhibitor to be purified. 9 More recently, we have demonstrated that an endogenous bufadienolide NKA inhibitor, marinobufagenin (MBG), 10 exhibits greater affinity for the ␣ 1 -NKA isoform than for the ouabain-sensitive ␣ 3 -isoform. 11-13 The ␣ 1 -NKA is the major isoform in the kidney, vascular smooth muscle, and adult cardiomyocytes. 14,15 Although phosphorylation of NKA by PKC can affect the sensitivity of this enzyme to ouabain, 16 it is not known whether PKC phosphorylation of specific NKA isoforms is implicated in NKA inhibition by endogenous digitalis-like inhibitors, such as MBG. We hypothesized that protein kinase C-induced phosphorylation of the NKA can potentiate the effect of endogenous digitalis-like ligands, and that such potentiation can ...

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12-Lipoxygenase Induces Apoptosis of Human Gastric Cancer AGS Cells via the ERK1/2 Signal Pathway

Chen

Wang

et al. 2007

Dig Dis Sci

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12-Lipoxygenase (12-LOX) is over-expressed in a variety of human tumors, but its exact effect on the tumorogenesis of gastric cancer remains largely obscure. To investigate the effect of 12-LOX and its inhibitor baicalein on proliferation and apoptosis of human gastric cancer, AGS cells were separately treated with 12-hydroxyeicosatetraenoic acid (12-HETE, a metabolite of 12-LOX) and baicalein. MTT assay revealed that the absorbance of the 12-HETE-treated group was significantly (P < 0.01) higher than that of control group and that the absorbance of baicalein-treated group was significantly (P < 0.01) less than that of the control group, and that 48 h after treatment the apoptosis index of the baicalein-treated group was significantly (P < 0.01) higher than that of the untreated group and was significantly (P < 0.01) lower in the 12-HETE-treated group. Western blotting analysis was used to investigate the mechanism of these effects. The results revealed that the concentration of phosphorylated ERK in cells treated with 100 nmol L(-1) 12-HETE was significantly (P < 0.05) higher than in the untreated group and that the concentration of phosphorylated ERK1/2 in cells treated with 40 micromol L(-1) baicalein was significantly (P < 0.05) lower than in the untreated group. The expression level of bcl-2 was up-regulated and down-regulated after separate treatment with 12-HETE and baicalein, respectively, and both of these effects could be blocked by PD98059. Protein kinase C (PKC) activity was increased by treatment with 12-HETE and reduced by treatment with baicalein (P < 0.05). The PKC inhibitor BIM (bisindolymaleimide-I) blocked the phosphorylation of ERK1/2 and activation of PKC induced by 12-LOX. When pretreated with BIM, the concentration of phospho-ERK1/2 or bcl-2 in the BIM + 12-HETE-treated group was significantly (P < 0.05) lower than in that treated with 12-HETE only, and the concentration in the BIM + baicalein-treated group was significantly (P < 0.05) higher than in that treated with baicalein only. On the basis of these data we conclude that, via its metabolite 12-HETE, 12-LOX abolishes proliferation of AGS cells and protect cells from apoptosis by activating the ERK1/2 pathway and, eventually, enhances expression of bcl-2. Because PKC is also involved in the activation of ERK1/2 induced by 12-LOX, 12-LOX inhibitors would be potentially powerful anticancer agents for prevention and cure of human gastric cancer.

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Cicletanine reverses vasoconstriction induced by the endogenous sodium pump ligand, marinobufagenin, via a protein kinase C dependent mechanism

Cited by 15 publications

References 33 publications

Myocardial PKC β2 and the Sensitivity of Na/K-ATPase to Marinobufagenin Are Reduced by Cicletanine in Dahl Hypertension

Myocardial PKC β2 and the Sensitivity of Na/K-ATPase to Marinobufagenin Are Reduced by Cicletanine in Dahl Hypertension

Phorbol Diacetate Potentiates Na ⁺ -K ⁺ ATPase Inhibition by a Putative Endogenous Ligand, Marinobufagenin

12-Lipoxygenase Induces Apoptosis of Human Gastric Cancer AGS Cells via the ERK1/2 Signal Pathway

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Cicletanine reverses vasoconstriction induced by the endogenous sodium pump ligand, marinobufagenin, via a protein kinase C dependent mechanism

Cited by 15 publications

References 33 publications

Myocardial PKC β2 and the Sensitivity of Na/K-ATPase to Marinobufagenin Are Reduced by Cicletanine in Dahl Hypertension

Myocardial PKC β2 and the Sensitivity of Na/K-ATPase to Marinobufagenin Are Reduced by Cicletanine in Dahl Hypertension

Phorbol Diacetate Potentiates Na + -K + ATPase Inhibition by a Putative Endogenous Ligand, Marinobufagenin

12-Lipoxygenase Induces Apoptosis of Human Gastric Cancer AGS Cells via the ERK1/2 Signal Pathway

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Phorbol Diacetate Potentiates Na ⁺ -K ⁺ ATPase Inhibition by a Putative Endogenous Ligand, Marinobufagenin