In this work, the role of the C5a anaphylatoxin receptor C5aR2 in two atherosclerosis models was examined. Cardiovascular diseases (CVDs) are the main cause of death in the industrialized western world. Atherosclerosis is the underlying pathophysiological cause for CVDs. It causes myocardial infarction, angina pectoris, sudden cardiac death and stroke. Atherosclerosis is an inflammatory disease of the arterial vessel wall and evolves mainly at site of disturbed blood flow as seen at bifurcations. The complement system is a part of the innate immune system and acts as a first line of defense against intruding pathogens. It has been shown to be involved in the initiation and progression of atherogenesis in humans and mice. Its activation triggers the cleavage of C5 into C5a and C5b. C5a is an anaphylatoxin, which signals through its two receptors C5aR1 and C5aR2. It was shown for C5aR1 to be implicated in atherosclerosis where it facilitates atherogenesis. On the other hand, it was demonstrated that expression of the C5aR2 in human correlates with the stage of atherogenesis. Nevertheless, the contribution of C5aR2 in atherosclerosis remains mainly unexplored. Thus, the aim of this study was to identify the role of C5aR2 in two independent mouse models of chronic diet induced or acute injury induced atherosclerosis and the underlying processes regulated and effected by C5aR2. For both approaches a C5ar2-/-/Apoe-/- mouse model was used, with a hyperlipidemic Apoe-/- background.To investigate the underlying processes and mechanisms and the C5aR2 contribution to atherogenesis, gene expression of pro inflammatory cytokines and adhesion molecules, as well as the number of cells positive for pro inflammatory markers were analyzed In Both, the acute injury induced atherosclerosis and the chronic diet induced atherosclerosis, we found a reduced lesion size in C5ar2-/-/Apoe-/- compared to their corresponding Apoe-/- control mice. This reduction was accompanied by a more stable plaque phenotype. Analysis of the cellular composition and gene expression within the lesion also revealed a reduction in inflammatory cells and cytokines.Furthermore, in vitro analysis of bone marrow derived macrophages indicate that in C5ar2-/-/Apoe-/- macrophages a shift in the polarization towards an anti inflammatory M2 phenotype occurs, which results in a reduction in pro inflammatory cytokine and adhesion molecule expression. On the other hand, systemic analysis demonstrated an increase in blood triglyceride and a reduction of cholesterol levels. Additionally, in the liver of C5ar2-/-/Apoe-/- mice elevated expression levels of pro inflammatory cytokines was found which might be a stress response of the liver to the elevated systemic triglyceride levels.Finally, to investigate the cooperative effect of blocking both C5a receptors, C5ar2-/-/Apoe-/- mice which underwent endothelial denudation additionally were implanted an osmotic mini pump equipped with a C5aR1 blocking inhibitor (C5aR1 A). Analysis of the carotid arteries revealed a further reduction in lesion size in C5aR1 A treated C5ar2-/-/Apoe-/- mice. This also manifests in a reduced macrophage number and pro inflammatory cytokine and adhesion molecule expression, whereas SMC numbers stay unchanged. Taken together, these data indicate that manipulating both receptors for C5a could provide an additional beneficial effect in handling atherosclerosis and restenosis. In summary, the shown data demonstrate that the C5aR2 is a functional receptor acting in a pro atherogenic manner on the progression and initiation of atherosclerosis. C5R2 induces pro inflammatory cytokine expression and inflammatory cell recruitment, which may be the cause how C5aR2 is mediating the atherogenic effect. This makes C5aR2 a suitable candidate for future drug targeting in order to handle atherosclerosis and restenosis. Nevertheless, further experiments are needed to clarify the exact mechanism of how C5aR2 is mediating the pro atherogenic effect
