JNK and c-Jun but not ERK and c-Fos are associated with sustained neointima-formation after balloon injury.
BACKGROUND
Formation of neointima after balloon angioplasty is regulated via inducible transcription factors (ITF), such as c-Jun and c-Fos, depending on mitogen activated protein (MAP) kinases, which have been shown to be activated after balloon injury. The precise localization of activated MAP-kinases and concomitant expression of transcription factors in the vessel wall remains to be elucidated. We have now studied the localization and time-dependent expression of MAP-kinases together with corresponding ITFs in the rat carotid angioplasty model.


METHODS
Animals were sacrificed at 0. 5, 6 and 24 h and 3, 5, 7, 14 and 28 days after injury. Cryocut sections were stained using antibodies directed against c-Jun, phosphorylated c-Jun, c-Fos, c-Jun amino-terminal kinase (JNK), extracellular signal related kinase (ERK), von Willebrand factor, ki67 antigen, and alpha-actin.


RESULTS
c-Jun expression was strongly induced in smooth muscle cells (SMC) 30 min after injury and remained upregulated for 24 h, thereafter dropping to basal levels at day 3. Re-expression was observed at day 7 and 14 but not day 28. Expression patterns of JNK and phosphorylated c-Jun were highly congruent to that of c-Jun. In contrast, c-Fos expression was restricted to 30 min and, less pronounced than c-Jun and JNK, was visible after 7 days. Also, its expression was congruent with the presence of ERK.


CONCLUSIONS
These findings demonstrate a clear association between MAP-kinases and their transcription factor substrates in vivo with a predominant association of JNK and c-Jun with sustained SMC proliferation.
Watson
L
L
Universität Heidelberg, Germany.
Herdegen
T
T
Buschmann
T
T
Denger
S
S
Wende
P
P
Jahn
L
L
Kreuzer
J
J
D000818:Animals; D002404:Catheterization; D002455:Cell Division; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000032:analysis / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000032:analysis / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000032:analysis / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000473:pathology*
D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases