Systemic treatment with neuropeptide Y receptor Y1-antagonist enhances atherosclerosis and stimulates IL-12 expression in ApoE deficient mice

• Published in: Neuropeptides (Edinburgh) 2013-04, Vol.47 (2), p.67-73
• Main Authors: Jääskeläinen, A.E, Seppälä, S, Kakko, T, Jaakkola, U, Kallio, J
• Format: Article
• Language: English
• Subjects: Adipokines - blood; Advanced Basic Science; Animals; Aorta - metabolism; ApoE deficient mice; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Arginine - analogs & derivatives; Arginine - pharmacology; Atherosclerosis; Atherosclerosis - metabolism; Atherosclerosis - pathology; Cholesterol - blood; Diet, High-Fat; Endocrinology & Metabolism; Immunohistochemistry; Inflammation; Interleukin-12 - biosynthesis; Lipids - blood; Mice; Mice, Knockout; Muscle, Smooth, Vascular - metabolism; Neuropeptide Y; Plaque, Atherosclerotic - pathology; Real-Time Polymerase Chain Reaction; Receptors, Neuropeptide Y - antagonists & inhibitors; Vascular Cell Adhesion Molecule-1 - metabolism; Y1-antagonist
• ISSN: 0143-4179; 1532-2785
• DOI: 10.1016/j.npep.2012.11.001

Abstract Aims 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 8 weeks. The mice were injected with two doses of NPY (50 or 100 μg/kg) or Y1 receptor antagonist BIBP3226 (100 μg/kg) or vehicle intraperitoneally for 8 weeks. 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 (100 μg/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.