Abstract 3607: CCR3 Antagonism Inhibits Adventitial Mast Cell Accumulation and Plaque Development in ApoE Deficient Mice
Mast cells have been detected in the perivascular tissue of advanced and ruptured human atherosclerotic lesions, suggesting a role for adventitial mast cells in plaque destabilization. As the chemokine receptor CCR3 and its ligand eotaxin have been hypothesized to affect mast cell migration, we aimed in this study to investigate whether inhibition of CCR3 influences perivascular mast cell content during plaque development and thereby affects plaque morphology. Atherosclerotic carotid artery lesions were induced in ApoE−/− mice by perivascular collar placement and the mice received the CCR3 antagonist GW782415 at low dose (LD): 3 mg/kg/day (n=11) or high dose (HD): 30 mg/kg/day (n=9) as diet supplement or control diet (n=10). After 6 weeks, the plaques were analyzed for size and composition. Treatment of the mice with GW782415 resulted in a decrease in white blood cell levels after 6 weeks of treatment (control: 6.3 ± 0.7*106, LD: 4.7 ± 0.6*106 and HD: 3.1 ± 0.8*106 cells/mL, P<0.001). Interestingly, plaque size was reduced in a dose-dependent manner from 75 ± 10*103 μm2 in control mice to 58 ± 8*103 μm2 in the LD group and even to 50 ± 8*103 μm2 in the HD group (P<0.05), which corresponded with an increase in lumen size (control: 27 ± 6*103 μm2, LD: 43 ± 8*103 μm2 and HD: 47 ± 7*103 μm2, P<0.05). Media size and total vessel area did not differ between the groups. Furthermore, mast cells numbers were dose-dependently reduced from 7.7 ± 1.3 mast cells/mm2 adventitial tissue in control mice to 4.6 ± 0.8 and 3.8 ± 0.2 mast cells/mm2 adventitial tissue in the LD and HD group (P<0.05), respectively. Mast cell activation status did not differ between the groups, while also collagen content was not affected by treatment with the CCR3 antagonist. Macrophage content was reduced only in the HD group by 82% compared to the control mice as demonstrated with a MOMA-2 staining (P<0.05) and this corresponded with a reduction in peritoneal macrophages in the HD group (control: 38 ± 0.5% versus HD: 33 ± 0.2%, P<0.05). In conclusion, our data suggest that inhibition of the chemokine receptor CCR3 indeed results in reduced plaque progression by inhibition of mast cell and macrophage migration, identifying CCR3 inhibition as a new therapeutic approach in the prevention of cardiovascular diseases.