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+/-0.16x10(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.
Hamilton
J R
JR
Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia. Justin.Hamilton@med.monash.edu.au
Cornelissen
I
I
Mountford
J K
JK
Coughlin
S R
SR
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics* / Q000502:physiology; D050197:Atherosclerosis / Q000097:blood* / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism; D003433:Crosses, Genetic; D005260:Female; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology; D018179:Receptors, Thrombin / Q000235:genetics / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
D001057:Apolipoproteins E; D018179:Receptors, Thrombin; D013917:Thrombin; C112908:protease-activated receptor 4