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

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 mu g/kg) or Y1 receptor antagonist BIBP3226 (100 mu g/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 mu g/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. (C) 2012 Elsevier Ltd. All rights reserved.