TY - JOUR
T1 - Loss of biglycan enhances thrombin generation in Apolipoprotein E-deficient mice
T2 - Implications for inflammation and atherosclerosis
AU - Grandoch, Maria
AU - Kohlmorgen, Christina
AU - Melchior-Becker, Ariane
AU - Feldmann, Kathrin
AU - Homann, Susanne
AU - Müller, Julia
AU - Kiene, Lena Sophia
AU - Zeng-Brouwers, Jinyang
AU - Schmitz, Friederike
AU - Nagy, Nadine
AU - Polzin, Amin
AU - Gowert, Nina S.
AU - Elvers, Margitta
AU - Skroblin, Philipp
AU - Yin, Xiaoke
AU - Mayr, Manuel
AU - Schaefer, Liliana
AU - Tannock, Lisa R.
AU - Fischer, Jens W.
N1 - Publisher Copyright:
© 2016 American Heart Association, Inc.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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.
KW - atherosclerosis
KW - biglycan
KW - blood platelets
KW - inflammation
KW - thrombin
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U2 - 10.1161/ATVBAHA.115.306973
DO - 10.1161/ATVBAHA.115.306973
M3 - Article
C2 - 27034473
AN - SCOPUS:84962050631
SN - 1079-5642
VL - 36
SP - e41-e50
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 5
ER -