title: Genetic and pharmacological modifications of thrombin formation in apolipoprotein e-deficient mice determine atherosclerosis severity and atherothrombosis onset in a neutrophil-dependent manner.
abstract: BACKGROUND
  Variations in the blood coagulation activity, determined genetically or by medication, may alter atherosclerotic plaque progression, by influencing pleiotropic effects of coagulation proteases. Published experimental studies have yielded contradictory findings on the role of hypercoagulability in atherogenesis. We therefore sought to address this matter by extensively investigating the in vivo significance of genetic alterations and pharmacologic inhibition of thrombin formation for the onset and progression of atherosclerosis, and plaque phenotype determination.
  
  
  RESULTS
  We generated transgenic atherosclerosis-prone mice with diminished coagulant or hypercoagulable phenotype and employed two distinct models of atherosclerosis. Gene-targeted 50% reduction in prothrombin (FII(-/WT):ApoE(-/-)) was remarkably effective in limiting disease compared to control ApoE(-/-) mice, associated with significant qualitative benefits, including diminished leukocyte infiltration, altered collagen and vascular smooth muscle cell content. Genetically-imposed hypercoagulability in TM(Pro/Pro):ApoE(-/-) mice resulted in severe atherosclerosis, plaque vulnerability and spontaneous atherothrombosis. Hypercoagulability was associated with a pronounced neutrophilia, neutrophil hyper-reactivity, markedly increased oxidative stress, neutrophil intraplaque infiltration and apoptosis. Administration of either the synthetic specific thrombin inhibitor Dabigatran etexilate, or recombinant activated protein C (APC), counteracted the pro-inflammatory and pro-atherogenic phenotype of pro-thrombotic TM(Pro/Pro):ApoE(-/-) mice.
  
  
  CONCLUSIONS
  We provide new evidence highlighting the importance of neutrophils in the coagulation-inflammation interplay during atherogenesis. Our findings reveal that thrombin-mediated proteolysis is an unexpectedly powerful determinant of atherosclerosis in multiple distinct settings. These studies suggest that selective anticoagulants employed to prevent thrombotic events may also be remarkably effective in clinically impeding the onset and progression of cardiovascular disease.
authors: Laboratory for Clinical Thrombosis and Hemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands. j.ilcheff@maastrichtuniversity.nl
authors: Julian I
authors: JI
authors: Borissoff
authors: Jeroen J T
authors: JJ
authors: Otten
authors: Sylvia
authors: S
authors: Heeneman
authors: Peter
authors: P
authors: Leenders
authors: René
authors: R
authors: van Oerle
authors: Oliver
authors: O
authors: Soehnlein
authors: Sarah T B G
authors: ST
authors: Loubele
authors: Karly
authors: K
authors: Hamulyák
authors: Tilman M
authors: TM
authors: Hackeng
authors: Mat J A P
authors: MJ
authors: Daemen
authors: Jay L
authors: JL
authors: Degen
authors: Hartmut
authors: H
authors: Weiler
authors: Charles T
authors: CT
authors: Esmon
authors: Joanne
authors: J
authors: van Ryn
authors: Erik A L
authors: EA
authors: Biessen
authors: Henri M H
authors: HM
authors: Spronk
authors: Hugo
authors: H
authors: ten Cate
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D000069604:Dabigatran; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006410:Hematopoiesis; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism*; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000188:drug therapy / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D017382:Reactive Oxygen Species; D013917:Thrombin / Q000235:genetics / Q000378:metabolism*; D013927:Thrombosis / Q000188:drug therapy / Q000209:etiology*
chemical_list: D001057:Apolipoproteins E; D001562:Benzimidazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D013917:Thrombin; D000069604:Dabigatran