Systemic treatment with neuropeptide Y receptor Y1-antagonist enhances atherosclerosis and stimulates IL-12 expression in ApoE deficient mice
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Updated: May 15, 2026
Quantitative Analysis of Cellular Composition in Advanced Atherosclerotic Lesions of Smooth Muscle Cell Lineage-Tracing Mice
Published on: February 20, 2019
A E Jääskeläinen1, S Seppälä, T Kakko
1Centre for Biotechnology, Tykistökatu 6A, University of Turku, Turku, Finland.
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.
Insights
Y1 receptor antagonist BIBP3226 worsened atherosclerosis in ApoE(-/-) mice, increasing lesion areas and interleukin-12 (IL-12) production. This suggests Y1 ligands may not be ideal for treating atherosclerosis.
Area of Science:
- Cardiovascular Research
- Immunology
- Pharmacology
Background:
- Neuropeptide Y (NPY) and its Y1 receptor are implicated in atherosclerosis.
- Understanding their role is crucial for developing new therapeutic strategies.
Purpose of the Study:
- To investigate the impact of NPY and Y1 receptor antagonism on atherosclerosis development.
- To analyze associated inflammatory markers in a mouse model.
Main Methods:
- ApoE(-/-) mice were fed a high-fat diet for 8 weeks.
- Mice received NPY or Y1 antagonist BIBP3226 (100μg/kg) or vehicle.
- Atherosclerosis, inflammatory molecules, and NPY levels were assessed.
Main Results:
- BIBP3226 significantly increased atherosclerotic lesion areas in descending aortas.
- Interleukin-12 (IL-12) expression in spleen and liver increased 8-fold with BIBP3226.
- Serum cholesterol correlated with VCAM-1 and inversely with NPY in the aortic wall.
Conclusions:
- Systemic Y1-antagonist treatment exacerbates atherosclerosis in ApoE(-/-) mice.
- This effect is linked to increased IL-12 production.
- Findings question the therapeutic potential of Y1 ligands for atherosclerosis.
