Involvement of mitogen-activated protein kinase signaling in growth and rupture of human intracranial aneurysms.
OBJECTIVE
Mitogen-activated protein kinases (MAPKs) are involved in vascular wall remodeling, but their role in the pathogenesis of intracranial aneurysms (IAs) is poorly known. We investigated the expression and phosphorylation of the 3 major mitogen-activated protein kinases, c-Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase, in unruptured and ruptured human IAs.


METHODS
Tissue samples (n=24, 12 unruptured and 12 ruptured IAs) were obtained during microneurosurgical clipping. The localization of the proteins was studied by immunofluorescent staining, and protein levels and phosphorylation state were studied by Western blotting.


RESULTS
The phosphorylation of p54 JNK was increased 1.5-fold in ruptured IAs and the phospho-p54 JNK level and its phosphorylation state directly correlated with IA size. The levels of phosphorylated and total levels of p38 were associated with IA size as well. Extracellular signal-regulated kinase did not associate with IA size or rupture status. Expression of transcription factor c-Jun, a downstream target of JNK, correlated with p54 JNK level and phosphorylation state. Furthermore, the levels of matrix metalloproteinase 9, known to have a role in vessel wall degeneration, correlated with p54 JNK phosphorylation in unruptured IAs and its expression was increased 4.3-fold in ruptured IAs.


CONCLUSIONS
Our results suggest that JNK activity and expression are involved in IA growth and possibly rupture and p38 expression in IA growth. Thus, pharmacological therapy affecting the stress-activated mitogen-activated protein kinases, JNK and p38, may enhance the repair of the IA wall in the future.
Laaksamo
Elisa
E
Biomedicum Helsinki, Helsinki University Central Hospital, Helsinki, Finland. elisa.laaksamo@helsinki.fi
Tulamo
Riikka
R
Baumann
Marc
M
Dashti
Reza
R
Hernesniemi
Juha
J
Juvela
Seppo
S
Niemelä
Mika
M
Laakso
Aki
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017542:Aneurysm, Ruptured / Q000201:enzymology / Q000209:etiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9