Abstract
In cultured rat vascular smooth muscle cells, angiotensin II (Ang II) induced a rapid increase in mitogen-activated protein kinase (MAPK) activity through the Ang II type 1 receptor, which was insensitive to pertussis toxin but was abolished by the phospholipase C inhibitor, U73122. The Ang II-induced MAPK activation was not affected by the protein kinase C inhibitor, GF109203X, and was only partially impaired by pretreatment with a phorbol ester, whereas both treatments completely prevented MAPK activation by the phorbol ester. Intracellular Ca2+ chelation by TMB-8, but not extracellular Ca2+ chelation or inhibition of Ca2+ influx, abolished Ang II-induced MAPK activation. The calmodulin inhibitor, calmidazolium, and the tyrosine kinase inhibitor, genistein, completely blocked MAPK activation by Ang II as well as by the Ca2+ ionophore A23187. Ang II caused a rapid increase in the binding of GTP to p21(ras), and this was inhibited by genistein, TMB-8, and calmidazolium but not by pertussis toxin or GF109203X. These data suggest that Ang II-induced MAPK activation through the Ang II type 1 receptor could be mediated by p21(ras)activation through a currently unidentified tyrosine kinase that lies downstream of Gq-coupled Ca2+/calmodulin signals.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Triphosphate / metabolism
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Amino Acid Sequence
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Angiotensin II / pharmacology*
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Animals
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Aorta, Thoracic
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Calcimycin / pharmacology
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Calcium / metabolism
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cells, Cultured
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Estrenes / pharmacology
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GTP-Binding Proteins / metabolism*
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Gallic Acid / analogs & derivatives
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Gallic Acid / pharmacology
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Genistein
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Imidazoles / pharmacology
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Indoles / pharmacology
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Isoflavones / pharmacology
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Kinetics
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Maleimides / pharmacology
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Molecular Sequence Data
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / enzymology
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Muscle, Smooth, Vascular / physiology*
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Peptides / chemical synthesis
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Peptides / metabolism
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Pertussis Toxin
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Protein Kinase C / antagonists & inhibitors
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Proto-Oncogene Proteins p21(ras) / metabolism*
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Pyrrolidinones / pharmacology
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Rats
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Rats, Sprague-Dawley
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Signal Transduction
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Substrate Specificity
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Type C Phospholipases / antagonists & inhibitors
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Virulence Factors, Bordetella / pharmacology
Substances
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Enzyme Inhibitors
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Estrenes
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Imidazoles
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Indoles
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Isoflavones
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Maleimides
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Peptides
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Pyrrolidinones
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Virulence Factors, Bordetella
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Angiotensin II
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1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
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Calcimycin
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calmidazolium
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8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate
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Gallic Acid
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Adenosine Triphosphate
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Genistein
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Pertussis Toxin
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Protein Kinase C
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Calcium-Calmodulin-Dependent Protein Kinases
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Type C Phospholipases
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GTP-Binding Proteins
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Proto-Oncogene Proteins p21(ras)
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bisindolylmaleimide I
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Calcium