© 2000 American Heart Association, Inc.
Molecular Medicine |
Angiotensin II Activates Nuclear Transcription Factor 
B Through AT1 and AT2 in Vascular Smooth Muscle Cells
Molecular Mechanisms
From the Vascular and Renal Research Laboratory (M.R.-O., O.L., M.R., J.E.), Fundación Jimenez Diaz, Universidad Autónoma Madrid, Spain, and Department of Molecular Biology and Bioinformatics (S.K., B.W.), Freie Universität Berlin, Germany.
Correspondence to Marta Ruiz-Ortega, PhD, Renal and Vascular Research Laboratory, Fundación Jiménez Díaz, Avda Reyes Católicos 2, 28040 Madrid, Spain. E-mail mruizo{at}fjd.es
Abstract—Nuclear factor-
B
(NF-B) regulates many genes involved in vascular physiopathology. We
have previously observed in vivo NF-B activation in injured vessels
that diminished by angiotensin-converting enzyme
inhibition. In the present work, we investigated the effect of
angiotensin II (Ang II) on NF-B activity in rat
vascular smooth muscle cells, evaluating the molecular mechanisms and
the specific receptor subtype involved. Ang II increased NF-B DNA
binding (5-fold, 10-9 mol/L at 1 hour;
electrophoretic mobility shift assay), nuclear translocation of
p50/p65 subunits, and cytosolic inhibitor B
(IB)
degradation. Ang II elicited NF-B–mediated transcription
(transfection of a reporter gene) and expression of NF-B–related
genes (monocyte chemoattractant protein-1 and
angiotensinogen). AT1 (DUP753) and
AT2 (PD123319 and CGP42112) receptor
antagonists inhibited Ang II–induced NF-B DNA binding
in a dose-dependent manner (
85% for each one;
10-5 mol/L at 1 hour). The AT2
agonist p-aminophenylalanine6–Ang II
augmented NF-B binding (4.6-fold, 10-9
mol/L at 1 hour), p65 nuclear levels, and transcription of an NF-B
reporter gene. AT1 antagonist markedly
inhibited NF-B–mediated transcription and gene expression. Some
differences between AT1/AT2 intracellular
signals were found. Antioxidants and ceramide inhibitors,
but not protein kinase C inhibitors, diminished NF-B
activation elicited by both Ang II and the AT2 agonist,
while tyrosine kinase inhibitors only decreased Ang
II–induced NF-B activity. Our results demonstrate that Ang II
activates NF-B via AT1 and AT2,
although NF-B–mediated transcription occurred mainly through
AT1. Both receptors share some signaling pathways (oxygen
radicals and ceramide); however, tyrosine kinases only participate in
AT1/NF-B responses. These data provide novel insights
into Ang II actions, suggesting a potential implication of the
AT2 in the pathobiology of vascular cells.
Key Words: angiotensin II • nuclear factor-B • receptors • vascular smooth muscle cell
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