Phorbol diacetate potentiates Na+-K+ ATPase inhibition by a putative endogenous ligand, marinobufagenin

Olga V. Fedorova, Natalia A. Dorofeeva, Denis A. Lopatin, Edward Lakatta, Alexei Y. Bagrov

Research output: Contribution to journalArticle

Abstract

Several vasoconstrictor agents can regulate the phosphorylation status of the Na+-K+ ATPase (NKA). We have recently demonstrated that mammalian tissues contain an endogenous bufadienolide, digitalis-like α1-NKA-selective ligand, marinobufagenin (MBG). Protein kinase C induces phosphorylation of the α1-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 α1-NKA from human mesenteric artery (HMA) sarcolemma and rat kidney but not that of the α3-NKA from rat fetal brain. In HMA Sarcolemma, which predominantly contains α1-NKA, PDA (50 nmol/L) potentiated the NKA-inhibitory effect of MBG at the level of high-affinity binding sites (0.05±0.03 nmol/L versus 4.0±1.7 nmol/L, P<0.05). In contrast, PDA did not affect the NKA inhibition by ouabain, an α3-NKA ligand. In isolated endothelium-denuded HMA artery rings, 50 nmol/L PDA potentiated the MBG-induced vasoconstriction (EC50, 17±6 nmol/L versus 150±40 nmol/L; P<0.01). Our results suggest that α1-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.

Original languageEnglish (US)
Pages (from-to)298-302
Number of pages5
JournalHypertension
Volume39
Issue number2 I
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Ligands
Protein Kinase C
Phosphorylation
Mesenteric Arteries
Digitalis
Protein Isoforms
Sarcolemma
Vasoconstrictor Agents
marinobufagenin
phorbol
sodium-translocating ATPase
Kidney
Ouabain
Vasoconstriction
Vascular Smooth Muscle
Smooth Muscle Myocytes
Endothelium
Arteries
Binding Sites
Hypertension

Keywords

  • Blood pressure
  • Bufanolides
  • Drug therapy
  • Na-K-exchanging ATPase
  • Ouabain
  • Protein kinases
  • Vasoconstriction

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Phorbol diacetate potentiates Na+-K+ ATPase inhibition by a putative endogenous ligand, marinobufagenin. / Fedorova, Olga V.; Dorofeeva, Natalia A.; Lopatin, Denis A.; Lakatta, Edward; Bagrov, Alexei Y.

In: Hypertension, Vol. 39, No. 2 I, 2002, p. 298-302.

Research output: Contribution to journalArticle

Fedorova, Olga V. ; Dorofeeva, Natalia A. ; Lopatin, Denis A. ; Lakatta, Edward ; Bagrov, Alexei Y. / Phorbol diacetate potentiates Na+-K+ ATPase inhibition by a putative endogenous ligand, marinobufagenin. In: Hypertension. 2002 ; Vol. 39, No. 2 I. pp. 298-302.
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T1 - Phorbol diacetate potentiates Na+-K+ ATPase inhibition by a putative endogenous ligand, marinobufagenin

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AU - Dorofeeva, Natalia A.

AU - Lopatin, Denis A.

AU - Lakatta, Edward

AU - Bagrov, Alexei Y.

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N2 - Several vasoconstrictor agents can regulate the phosphorylation status of the Na+-K+ ATPase (NKA). We have recently demonstrated that mammalian tissues contain an endogenous bufadienolide, digitalis-like α1-NKA-selective ligand, marinobufagenin (MBG). Protein kinase C induces phosphorylation of the α1-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 α1-NKA from human mesenteric artery (HMA) sarcolemma and rat kidney but not that of the α3-NKA from rat fetal brain. In HMA Sarcolemma, which predominantly contains α1-NKA, PDA (50 nmol/L) potentiated the NKA-inhibitory effect of MBG at the level of high-affinity binding sites (0.05±0.03 nmol/L versus 4.0±1.7 nmol/L, P<0.05). In contrast, PDA did not affect the NKA inhibition by ouabain, an α3-NKA ligand. In isolated endothelium-denuded HMA artery rings, 50 nmol/L PDA potentiated the MBG-induced vasoconstriction (EC50, 17±6 nmol/L versus 150±40 nmol/L; P<0.01). Our results suggest that α1-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.

AB - Several vasoconstrictor agents can regulate the phosphorylation status of the Na+-K+ ATPase (NKA). We have recently demonstrated that mammalian tissues contain an endogenous bufadienolide, digitalis-like α1-NKA-selective ligand, marinobufagenin (MBG). Protein kinase C induces phosphorylation of the α1-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 α1-NKA from human mesenteric artery (HMA) sarcolemma and rat kidney but not that of the α3-NKA from rat fetal brain. In HMA Sarcolemma, which predominantly contains α1-NKA, PDA (50 nmol/L) potentiated the NKA-inhibitory effect of MBG at the level of high-affinity binding sites (0.05±0.03 nmol/L versus 4.0±1.7 nmol/L, P<0.05). In contrast, PDA did not affect the NKA inhibition by ouabain, an α3-NKA ligand. In isolated endothelium-denuded HMA artery rings, 50 nmol/L PDA potentiated the MBG-induced vasoconstriction (EC50, 17±6 nmol/L versus 150±40 nmol/L; P<0.01). Our results suggest that α1-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.

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KW - Drug therapy

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KW - Ouabain

KW - Protein kinases

KW - Vasoconstriction

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