Abstract 5577: Complement Component 3a Receptor (C3aR) Attenuates Atherosclerosis Development
Up-to-date molecular biological methods permit efficient identification and characterization of new genes. Using Affimetrix microarrays, we studied gene expression in thoracic aorta of ApolipoproteinE−/− (ApoE−/−) animals fed either a normal or a high cholesterol diet (HCD) for 4 weeks. Over 200 genes were differentially regulated under these conditions. Interestingly, most components of the complement pathway were upregulated after a HCD, with the complement component 3a receptor (C3aR) exhibiting the highest induction. To study the relevance of the complement pathway in atherogenesis, ApoE−/−C3aR−/− mice and ApoE−/− controls were compared after 12 weeks of a HCD. ApoE−/−C3aR−/− animals had on average 14.11%±3.16% of descending aortas occupied by atherosclerotic plaques, which was nearly 2-fold more than controls (7.11%±1.01%). This effect was associated with increased accumulation of leukocytes in atherosclerotic plaques of ApoE−/−C3aR−/− mice. Moreover, production of the proinflammatory cytokines interferon gamma (IFNγ), chemokine (C-C) ligand-5 (CCL5), tumor necrosis factor beta (TNFβ), interleukin-12 (IL-12), and interleukin-18 (IL-18) was higher upon C3aR deletion. This study demonstrates that C3aR protects from atherosclerosis development, emphasizing the complex role of the complement cascade in the development of inflammation during atherogenesis.