Faculty Collaboration Database

Genetic and pharmacological modifications of thrombin formation in apolipoprotein e-deficient mice determine atherosclerosis severity and atherothrombosis onset in a neutrophil-dependent manner. PLoS One 2013;8(2):e55784

Date

02/15/2013

Pubmed ID

23409043

Pubmed Central ID

PMC3567111

DOI

10.1371/journal.pone.0055784

Scopus ID

2-s2.0-84873592215 (requires institutional sign-in at Scopus site)   104 Citations

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.

METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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.

Author List

Borissoff JI, Otten JJ, Heeneman S, Leenders P, van Oerle R, Soehnlein O, Loubele ST, Hamulyák K, Hackeng TM, Daemen MJ, Degen JL, Weiler H, Esmon CT, van Ryn J, Biessen EA, Spronk HM, ten Cate H

Author

Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Apolipoproteins E
Atherosclerosis
Benzimidazoles
Blood Coagulation
Dabigatran
Disease Models, Animal
Disease Progression
Female
Hematopoiesis
Inflammation
Mice
Mice, Knockout
Neutrophils
Phenotype
Plaque, Atherosclerotic
Pyridines
Reactive Oxygen Species
Thrombin
Thrombosis