Protective role for calcitonin gene-related peptide in atherosclerosis progress in ApoE knockout mice

The calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide, and its various functions such as being a potent vasodilator, being a cytoprotectant, and inhibiting macrophage infiltration have been reported. However, its role in atherosclerosis remains unclear. We investigated whether CGRP has a role in atherosclerosis development in apolipoprotein E–deficient mice. We have previously reported double-knockout ApoE−/−:CGRP−/− (DKO) mice, increased serum cholesterol levels, atherosclerotic plaque areas, and migration functions in peritoneal macrophages with increase in the level of inflammatory cytokine TNFα. Herein, we investigated whether inactivating TNFα improves atherosclerosis in DKO mice. We also investigated whether results similar with those of DKO could be obtained by administering a humanized monoclonal CGRP antibody, galcanezumab, to ApoE knockout (ApoE KO) mice. ApoE KO male mice and DKO male mice were fed a high-fat diet for 8 weeks, and effects on lesion size and macrophage functions were assessed after 2 weeks. The etanercept was intraperitoneally administered once a week (5 mg/kg), which caused significant reduction in the aortic root and atherosclerotic plaque area in DKO mice. ApoE KO mice were subcutaneously administered with galcanezumab once a week (50 mg/kg). Furthermore, TNFα inhibition reduced the macrophage migration. The galcanezumab increased atherosclerotic lesions similar in DKO mice. These results suggested that CGRP plays a critical role in inhibitory effect on atherosclerosis progression.