TY - JOUR
T1 - Phorbol diacetate potentiates Na+-K+ ATPase inhibition by a putative endogenous ligand, marinobufagenin
AU - Fedorova, Olga V.
AU - Dorofeeva, Natalia A.
AU - Lopatin, Denis A.
AU - Lakatta, Edward G.
AU - Bagrov, Alexei Y.
PY - 2002
Y1 - 2002
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.
KW - Blood pressure
KW - Bufanolides
KW - Drug therapy
KW - Na-K-exchanging ATPase
KW - Ouabain
KW - Protein kinases
KW - Vasoconstriction
UR - http://www.scopus.com/inward/record.url?scp=0036175988&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036175988&partnerID=8YFLogxK
U2 - 10.1161/hy0202.104344
DO - 10.1161/hy0202.104344
M3 - Article
C2 - 11847201
AN - SCOPUS:0036175988
SN - 0194-911X
VL - 39
SP - 298
EP - 302
JO - Hypertension
JF - Hypertension
IS - 2 I
ER -