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Medline ® Abstract for Reference 77

of 'Actions of angiotensin II on the heart'

Angiotensin blockade inhibits activation of mitogen-activated protein kinases in rat balloon-injured artery.
Kim S, Izumi Y, Yano M, Hamaguchi A, Miura K, Yamanaka S, Miyazaki H, Iwao H
Circulation. 1998;97(17):1731.
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.
Department of Pharmacology, Osaka City University Medical School, Osaka, Japan. kims@msic.med.osaka-cu.ac.jp