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Updated: Mar 23, 2026
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Loss of Biglycan Enhances Thrombin Generation in Apolipoprotein E-Deficient Mice: Implications for Inflammation and
Maria Grandoch1, Christina Kohlmorgen1, Ariane Melchior-Becker1
1From the Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (M.G., C.K., A.M.-B., K.F., S.H., J.M., L.-S.K., F.S., N.N., J.W.F.); Cardiovascular Research Institute Düsseldorf (CARID), Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (M.G., C.K., A.M.-B., K.F., S.H., J.M., L.-S.K., F.S., N.N., A.P., J.W.F.); Klinik für Kardiologie, Pneumologie und Angiologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (A.P.); Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der Goethe-Universität, Frankfurt am Main, Germany (J.Z.-B., L.S.); Institut für Hämostaseologie, Hämotherapie und Transfusionsmedizin, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (N.S.G., M.E.); King's British Heart Foundation Centre, King's College London, London, United Kingdom (P.S., X.Y., M.M.); and Division of Endocrinology and Molecular Medicine, Saha Cardiovascular Research Center, University of Kentucky, Lexington (L.R.T.).
Objective:
Thrombin signaling promotes atherosclerosis by initiating inflammatory events indirectly through platelet activation and directly via protease-activated receptors. Therefore, endogenous thrombin inhibitors may be relevant modulators of atheroprogression and cardiovascular risk. In addition, endogenous thrombin inhibitors may affect the response to non-vitamin K-dependent oral anticoagulants. Here, the question was addressed whether the small leucine-rich proteoglycan biglycan acts as an endogenous thrombin inhibitor in atherosclerosis through activation of heparin cofactor II.
Approach And Results:
Biglycan concentrations were elevated in the plasma of patients with acute coronary syndrome and in male Apolipoprotein E-deficient (ApoE(-/-)) mice. Biglycan was detected in the glycocalyx of capillaries and the subendothelial matrix of arterioles of ApoE(-/-) mice and in atherosclerotic plaques. Thereby a vascular compartment is provided that may mediate the endothelial and subendothelial activation of heparin cofactor II through biglycan. ApoE and Bgn double-deficient (ApoE(-/-)/Bgn(-/0)) mice showed higher activity of circulating thrombin, increased platelet activation and platelet adhesion in vivo, supporting a role of biglycan in balancing thrombin activity. Furthermore, concentrations of circulating cytokines and aortic macrophage content were elevated in ApoE(-/-)/Bgn(-/0) mice, suggesting a proinflammatory phenotype. Elevated platelet activation and macrophage accumulation were reversed by treating ApoE(-/-)/Bgn(-/0) mice with the thrombin inhibitor argatroban. Ultimately, ApoE(-/-)/Bgn(-/0) mice developed aggravated atherosclerosis.
Conclusions:
The present results indicate that biglycan plays a previously unappreciated protective role during the progression of atherosclerosis by inhibiting thrombin activity, platelet activation, and finally macrophage-mediated plaque inflammation.
