Protective effects of C5a receptor antagonism in a mouse model of atherosclerosis

Inflammation is a major factor in the initiation and progression of atherosclerosis. Complement activation product 5a (C5a) is central to the pathology of many inflammatory diseases, and the C5a receptor (C5aR) antagonist PMX53 has been shown to be effective in reducing C5a-mediated inflammation in a number of these. While C5aR has been detected in atherosclerotic lesions, to date no studies examining C5aR antagonism in an animal model of atherosclerosis have been performed. We are studying the therapeutic benefits of inhibiting C5a, using PMX53 in the ApoE knockout (ApoE−/−) mouse model of atherosclerosis. To establish which cells respond to C5a, rat smooth muscle cells (SMC) and human monocyte-derived macrophages (HMDM) were grown in culture. SMC expressed mRNA and protein for C5aR (KD = 301.5 pM, receptor density of 26,600 sites/cell) and the second receptor for C5a, C5L2. Human monocytes also expressed these receptors. HMDM bound C5a and PMX53 with high affinity (2.8 and 82 nM, respectively). After establishing the presence of receptors for C5a in ApoE−/− mice, further mice were given a normal chow diet and treated for 25 weeks with PMX53 (1 mg/kg; tri-weekly s.c.). After this time, mice were terminated and the brachiocephalic artery, aortic root and aorta removed for histological analysis. PMX53-treated animals had smaller lesions in both the brachiocephalic artery and aortic root compared with untreated animals. Experiments are currently underway to determine if there are other changes associated with PMX53 treatment in this model. We are also testing the effects of C5aR antagonism in a more aggressive model of atherosclerosis, the fat-fed ApoE−/− mouse. In conclusion, this is the first study to demonstrate the potential benefits of specifically inhibiting C5a in a mouse model of atherosclerosis. These findings suggest that C5a plays a role in atherogenesis and that the C5aR antagonist PMX53 may be of therapeutic benefit in human disease