Abstract 12495: Enhanced Thrombin Activity in Biglycan-deficient Mice Promotes Vascular Inflammation in Murine Atherosclerosis
Introduction:Thrombin signalling initiates inflammatory events directly and through activation of platelets. Endogenous and pharmacologic inhibitors of thrombin are therefore of relevance during atheroprogression and for therapeutic intervention. The small leucine-rich proteoglycan biglycan (BGN) is thought to inhibit thrombin activity by activation of heparin cofactor II. Hypothesis: Genetic deletion of BGN affects thrombin activity, inflammation and atherosclerosis. Methods:Male mice deficient in apolipoprotein E and BGN (ApoE-/-/Bgn-/0) were compared with their ApoE-/- littermates.
Results: In ApoE-/- mice BGN was detected in the plasma and subendothelial matrix of capillaries, arterioles and in atherosclerotic plaques. In line with a role of BGN in balancing thrombin activity, ApoE-/-/Bgn-/0 mice exhibited higher activity of circulating thrombin and greater platelet activation than did ApoE-/- mice. Furthermore, higher concentrations of circulating cytokines in ApoE-/-/Bgn-/0 mice suggested a proinflammatory phenotype. Accordingly, isolated peritoneal macrophages released elevated concentrations of proinflammatory cytokines in response to Toll-like receptor stimulation. Immunohistochemistry and FACS analysis of the aorta demonstrated increased macrophage content in atherosclerotic lesions. Furthermore, ApoE-/-/Bgn-/0 mice exhibited higher aortic plaque burden and larger atherosclerotic lesions at the aortic root. Treatment with the thrombin inhibitor argatroban reversed platelet activation and aortic macrophage accumulation in ApoE-/-/Bgn-/0 mice. Finally, ApoE-/-/Bgn-/0 mice exhibited progressive dilation of the aortic arch, a pathological finding corroborated by markedly reduced collagen fibril density.
Conclusions: The present results indicate that BGN plays a previously unappreciated protective role during progression of atherosclerosis by inhibiting thrombin activity and platelet activation, and ultimately macrophage-mediated plaque inflammation.
Author Disclosures: M. Grandoch: None. A. Melchior-Becker: None. K. Feldmann: None. J. Müller: None. C. Klatt: None. S. Homann: None. L. Dick: None. N. Nagy: None. L. Schäfer: None. P. Skroblin: None. X. Yin: None. M. Mayr: None. L. Tannock: None. J.W. Fischer: None.
- © 2015 by American Heart Association, Inc.