Atherosclerosis proceeds independently of thrombin-induced platelet activation in ApoE−/− mice

Platelet activation has long been postulated to contribute to the development of atherosclerotic plaques, although the mechanism by which this might occur remains unknown. Thrombin is a potent platelet activator and transfusion of thrombin-activated platelets into mice increases plaque formation, suggesting that thrombin-induced platelet activation might contribute to platelet-dependent atherosclerosis. Platelets from protease-activated receptor 4-deficient (Par4−/−) mice fail to respond to thrombin. To determine whether thrombin-activated platelets play a necessary role in a model of atherogenesis, we compared plaque formation and progression in Par4+/+ and Par4−/− mice in the atherosclerosis-prone apolipoprotein E-deficient (ApoE−/−) background. Littermate Par4+/+ and Par4−/− mice, all ApoE−/−, were placed on a Western diet (21% fat, 0.15% cholesterol) for 5 or 10 weeks. The percent of aortic lumenal surface covered by plaques in Par4+/+ and Par4−/− mice was not different at either time point (2.2 ± 0.3% vs. 2.5 ± 0.2% and 5.1 ± 0.4% vs. 5.6 ± 0.4% after 5 and 10 weeks, respectively). Further, no differences were detected in the cross-sectional area of plaques measured at the aortic root (1.53 ± 0.17 vs. 1.66 ± 0.16 × 105 μm2 and 12.56 ± 1.23 vs. 13.03 ± 0.55 × 105 μm2 after 5 and 10 weeks, respectively). These findings indicate that thrombin-mediated platelet activation is not required for the early development of atherosclerotic plaques in the ApoE−/− mouse model and suggest that, if platelet activation is required for plaque formation under these experimental conditions, platelet activators other than thrombin suffice.