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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 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. [Copyright &y& Elsevier]

Abstract: Aims: The role of neuropeptide Y (NPY) and its gene polymorphisms in the development of atherosclerosis has become increasingly evident. In asthma, NPY has been shown to be involved as immunomodulator. In this study, we investigated the role of two functional NPY polymorphisms, NPY-Leu7Pro (rs16139) and NPY-399C/T (rs16147) and obesity for the development of asthma as well as atherosclerosis in asthmatic and non-asthmatic subjects. Also, we measured heart rate variability (HRV) and NPY in serum since these might contribute through these polymorphisms to both diseases. Methods and results: Thousand hundred and seventy six Finnish young adults were genotyped and three groups (G1–G3) were formed based on the observed diplotypes. The NPY-Pro7 allele always co-existed with the NPY-399T allele indicating complete linkage disequilibrium. Here we show that overweight (BMI⩾25kg/m2) was associated with 2.5-fold increased risk for asthma in subjects with the NPY-399T allele without NPY-Pro7 allele (G2, n =716). Overweight was also associated with increased atherosclerosis determined by carotid intima media thickness (cIMT), but asthma seemed to be more significant determinant than overweight in determing cIMT having a decreasing effect. NPY concentration in serum was diplotype-driven (G1=792.2(29.5), G2=849.0(18.9), G3=873.9(45.2) pg/ml) and correlated positively with cIMT in the group having NPY-Pro7 allele (G3, n =142). However, the subjects with asthma had a negative NPY-cIMT relationship. Total HRV was increased in asthma and correlated negatively with cIMT irrespective of the NPY genotype. Conclusions: Overweight together with the NPY-399T allele without NPY-Pro7 allele was associated with increased risk for asthma. Atherosclerosis was decreased in subjects with asthma depending on the NPY genotype. The results reveal novel insights into the genetics and biology of the relationship of atherosclerosis and asthma. [Copyright &y& Elsevier]