A fibrinogen deficiency accelerates the initiation of LDL cholesterol-driven atherosclerosis via thrombin generation and platelet activation in genetically predisposed mice.
Mice with combined deficiencies of the low-density lipoprotein receptor (LDLR(-/-)) and the catalytic component of an apolipoprotein B-edisome complex (APOBEC1(-/-)) that converts apoB-100 to apoB-48 have been characterized, and this model of LDL cholesterol-driven atherosclerosis was applied to an investigation of the role of fibrinogen (Fg) in the genesis and progression of the plaque. LDLR(-/-)/APOBEC1(-/-)/FG(-/-) (L(-/-)/A(-/-)/FG(-/-)) triple-deficient mice presented more advanced plaque in their aortic trees and aortic sinuses at 24, 36, and 48 weeks of age compared to L(-/-)/A(-/-) mice, a feature that may result from enhanced platelet activation in these former mice. This is supported by the presence of hypercoagulability, increased CD61 and CD62P on resting platelets, and higher plasma soluble P-selectin in L(-/-)/A(-/-)/FG(-/-) mice as compared to L(-/-)/A(-/-), FG(-/-), or wild-type mice. The elevated higher molecular weight forms of von Willebrand factor (VWF) in L(-/-)/A(-/-)/FG(-/-) mice, revealed by increased VWF collagen binding activity, perhaps resulting from down-regulation of its cleaving metalloproteinase, ADAMTS13, further indicates enhanced platelet activation. Thus, the earlier arterial plaque deposition in L(-/-)/A(-/-)/FG(-/-) mice appears to contain a contribution from enhanced levels of thrombin and activated platelets, a synergistic consequence of an Fg deficiency combined with a high LDL cholesterol concentration.
Iwaki
Takayuki
T
W. M. Keck Center for Transgene Research, 230 Raclin-Carmichael Hall, University of Notre Dame, Notre Dame, IN 46556, USA.
Sandoval-Cooper
Mayra J
MJ
Brechmann
Markus
M
Ploplis
Victoria A
VA
Castellino
Francis J
FJ
D000071479:APOBEC-1 Deaminase; D000347:Afibrinogenemia / Q000235:genetics*; D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics* / Q000473:pathology; D001777:Blood Coagulation; D008078:Cholesterol, LDL / Q000235:genetics*; D003564:Cytidine Deaminase / Q000172:deficiency; D020022:Genetic Predisposition to Disease; D051379:Mice; D018345:Mice, Knockout; D015539:Platelet Activation; D011973:Receptors, LDL / Q000172:deficiency*; D013917:Thrombin / Q000378:metabolism*
D008078:Cholesterol, LDL; D011973:Receptors, LDL; D013917:Thrombin; D000071479:APOBEC-1 Deaminase; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase