From the Department of Pharmacology (S.K., Y.I., M.Y., A.H., K.M., S.Y.,
H.I.), Osaka City University Medical School, Osaka, Japan, and the Gene
Experiment Center and Center for Tsukuba Advanced Research Alliance (H.M.),
University of Tsukuba, Ibaraki, Japan.
Correspondence to Shokei Kim, MD, Department of Pharmacology, Osaka City University Medical School, 1–4-54 Asahimachi, Abeno, Osaka 545, Japan. E-mail kims{at}msic.med.osaka-cu.ac.jp
Background—The effect of balloon
injury on the arterial signal transduction pathway has not
been examined. In vitro studies show that extracellular
signal-regulated kinases (ERKs) and c-Jun NH2-terminal
kinases (JNKs), belonging to the mitogen-activated protein
kinase (MAPK) family, play a critical role in the activation of
transcription factor activator protein-1 (AP-1) and cell
proliferation or apoptosis. However, the activation and role of
MAPKs in vascular diseases in vivo remain to be determined. Therefore,
we examined the effect of balloon injury on arterial MAPKs
and the possible role of angiotensin II.
Methods and Results—Arterial JNK and ERK activities
were measured by in-gel kinase assay. AP-1 DNA binding activity was
determined by gel mobility shift analysis. After balloon injury
of rat carotid artery, JNK (p46JNK and p55JNK) and ERK (p44ERK and
p42ERK) activities were increased as early as 2 minutes, reached their
peak (6- to 18-fold) at 5 minutes, and thereafter rapidly declined to
control levels. JNK and ERK activations were followed by a 3.9-fold
increase in arterial AP-1 DNA binding activity, which
contained c-Jun and c-Fos proteins. Arterial JNK activation
at 2 or 5 minutes was remarkably suppressed by E4177 (an
angiotensin AT1 receptor antagonist) and
cilazapril (an ACE inhibitor). E4177 also prevented
activation of ERKs by suppressing their tyrosine
phosphorylation, whereas cilazapril failed to prevent
such activation. The increased AP-1 DNA binding activity was
significantly inhibited by both E4177 and cilazapril.
Conclusions—Arterial JNKs and ERKs are dramatically
activated by balloon injury associated with the activation of
the AP-1 complex. These MAPK activations, followed by AP-1 activation,
are mediated at least in part by the AT1 receptor. Thus, activation of
JNKs and ERKs may be responsible for balloon injury–induced
neointima formation.
© 1998 American Heart Association, Inc.
Basic Science Reports
Angiotensin Blockade Inhibits Activation of Mitogen-Activated Protein Kinases in Rat Balloon-Injured Artery
Key Words: angiotensin • balloon • signal transduction • muscle, smooth • remodeling
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