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Atherosclerosis. 2009 Aug;205(2):427-32. doi: 10.1016/j.atherosclerosis.2009.01.018. Epub 2009 Jan 23.

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

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  • 1Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.


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+/-0.16x10(5)microm(2) and 12.56+/-1.23 vs. 13.03+/-0.55x10(5)microm(2) 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.

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