Abstract 15194: Dabigatran Causes Remodelling of Plaque Extracellular-Matrix in Diabetogenic Low Density Lipoprotein-Receptor Knockout Mice
Thrombin plays a central role in thrombus formation and platelet aggregation and is critically involved in many processes known to promote vascular diseases, e.g. stimulation of smooth muscle cell proliferation, cell migration and chemoattraction of monocytes. Little is known about how pharmacological inhibition of thrombin might affect extracellular matrix (ECM) of atherosclerotic lesions. Aim of the present study was to investigate whether thrombin inhibition by dabigatran might show favourable effects on proteoglycan matrix of atherosclerotic lesions in a mouse model of diabetes and atherosclerosis. Low density lipoprotein-receptor deficient mice (8 weeks old) received a diabetogenic diet and were treated with 5 mg dabigatran etexilate /g chow or matching placebo for 20 weeks. Subsequently, the effects of dabigatran on the development of atherosclerotic lesions and ECM composition were determined at the aortic root. Treatment with dabigatran significantly inhibited atherosclerotic lesion formation in the aorta (11.23±1.14 % versus 6.84±1.06 %; n = 10). Furthermore, analysis of the aorta by qPCR revealed an increase in mRNA expression of the small leucine-rich proteoglycan biglycan known to positively regulate collagen fibrillogenesis. In addition, marked changes in matrix composition were observed in the aortic root: Importantly, the content of biglycan was significantly increased (21.35±4.14 % positive staining versus 33.75±4.16 % positive staining; n = 10). Furthermore birefringence analysis of Sirius red stained collagen using polarized light revealed increased amounts of tightly arranged collagen fibrils (11.92±2.06 % positive staining versus 19.60±2.67 % positive staining; n = 10). These results are in line with the finding that inhibition of thrombin may have plaque-stabilizing effects in apolipoprotein E-deficient mice likely mediated by anti-inflammatory mechanisms. In summary, the present changes of the proteoglycan and collagen matrix in a diabetic model of atherosclerosis strongly suggest that biglycan is a novel, pleiotropic target of dabigatran treatment. Functionally increased biglycan might contribute to the development of a stable plaque phenotype by increased condensation of collagen networks.
- © 2011 by American Heart Association, Inc.