title: Systemic treatment with neuropeptide Y receptor Y1-antagonist enhances atherosclerosis and stimulates IL-12 expression in ApoE deficient mice.
abstract: OBJECTIVE
  Neuropeptide Y (NPY) and Y1 receptors are involved in the mechanisms related to the development of atherosclerosis. We investigated the effects of systemically given NPY and its receptor Y1-antagonist on the development of atherosclerosis and associated inflammatory molecules in ApoE(-/-) mice during high-fat diet.
  
  
  METHODS
  Five weeks old ApoE(-/-) were fed atherogenic high cholesterol diet for 8weeks. The mice were injected with two doses of NPY (50 or 100μg/kg) or Y1 receptor antagonist BIBP3226 (100μg/kg) or vehicle intraperitoneally for 8weeks. Atherosclerosis lesion areas in aortic arch and descending aortas were determined, inflammatory molecules and NPY were determined in aortic wall, spleen, liver or in serum.
  
  
  RESULTS
  Neuropeptide Y1 receptor antagonist, BIBP3226 (100μg/kg) increased atherosclerotic lesion areas compared to vehicle in descending aortas in ApoE(-/-) mice (p=0.021). The expression levels of macrophage-derived cytokine, interleukin-12 (IL-12) in spleens and livers were 8-fold increased with BIBP3226 (p=0.006 and p=0.003, respectively) as determined by RT-qPCR. Cholesterol levels in serum correlated positively with VCAM-1 expression (p=0.003) and negatively with NPY expression (p=0.044) in aortic wall in mice treated with BIBP 3226.
  
  
  CONCLUSIONS
  The results indicate that systemic treatment with Y1-antagonist enhances atherosclerosis development in ApoE deficient mice by triggering an overwhelming IL-12 production. The findings are highly valuable for evaluation of the development potential of Y1 ligands for therapeutics to treat or prevent atherosclerosis.
authors.affiliation: Centre for Biotechnology, Tykistökatu 6A, University of Turku, Turku, Finland.
authors.forename: A E
authors.initials: AE
authors.lastname: Jääskeläinen
authors.forename: S
authors.initials: S
authors.lastname: Seppälä
authors.forename: T
authors.initials: T
authors.lastname: Kakko
authors.forename: U
authors.initials: U
authors.lastname: Jaakkola
authors.forename: J
authors.initials: J
authors.lastname: Kallio
mesh_terms: D054392:Adipokines / Q000097:blood; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat; D007150:Immunohistochemistry; D018664:Interleukin-12 / Q000096:biosynthesis*; D008055:Lipids / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D054392:Adipokines; D001057:Apolipoproteins E; C092926:BIBP 3226; D008055:Lipids; D017476:Receptors, Neuropeptide Y; D019010:Vascular Cell Adhesion Molecule-1; D018664:Interleukin-12; D001120:Arginine; D002784:Cholesterol