title: Involvement of mitogen-activated protein kinase signaling in growth and rupture of human intracranial aneurysms.
abstract: 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.
authors.affiliation: Biomedicum Helsinki, Helsinki University Central Hospital, Helsinki, Finland. elisa.laaksamo@helsinki.fi
authors.forename: Elisa
authors.initials: E
authors.lastname: Laaksamo
authors.forename: Riikka
authors.initials: R
authors.lastname: Tulamo
authors.forename: Marc
authors.initials: M
authors.lastname: Baumann
authors.forename: Reza
authors.initials: R
authors.lastname: Dashti
authors.forename: Juha
authors.initials: J
authors.lastname: Hernesniemi
authors.forename: Seppo
authors.initials: S
authors.lastname: Juvela
authors.forename: Mika
authors.initials: M
authors.lastname: Niemelä
authors.forename: Aki
authors.initials: A
authors.lastname: Laakso
mesh_terms: 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
chemical_list: 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