Abstract 1730: CD44-Deficiency does not Influence Atherogenesis in Low Density Lipoprotein Receptor-Deficient Mice but Affects Blood Clotting by Reduced Antithrombin Activity
The expression of adhesion molecule CD44 is elevated in human atherosclerosis and contributes to atherogenesis in ApoE−/− mice. The precise function of CD44 in advanced atherosclerosis is still unknown although CD44 is found at the plaque/thrombus interface in eroded human plaques. We investigated the role of CD44 in advanced atherosclerosis in LDLr−/− mice that either lack (CD44−/− ) or express CD44 and determined how CD44 influences thrombus formation. Mice were fed a Western diet for 20 weeks, followed by chow diet for another 10 weeks. Lesion development was determined by non-invasive ultrasound and en face technique. We found that mice exhibited hallmarks of stable lesions such as high expression of matrix components and smooth muscle cells and low content of macrophages. CD44-deficiency did neither affect late stage atherosclerotic lesion size nor structure in female (n = 15) or male (n = 13–15) mice (P > 0.05). CD44−/− plasma compaired with wild-type (Wt) controls displayed ~40% reduction in antithrombin levels (−1.38, n = 4, P= 0.0097) and ~14% less antithrombin activity (1.096 ± 0.084 vs. 1.28 ± 0.080 U/mL, n = 12; P=2x10−5). Blood clots of CD44−/− plasma were less elastic as seen by a frequency shift from 121 ± 44.9 Hz in Wt to 39.2 ± 15.3 Hz in CD44−/− plasma (n = 7–5, P= 0.002) determined by quartz cristall microbalance methodology. CD44-deficiency resulted in less thrombogenic plasma as suggested by the speed of clot formation (2.46 ± 1.28 vs. 4.76 ± 1.99 Hz/min; n = 7–5, P = 0.035). In addition, the viscoelastic properties of the adhesion layer shows that CD44−/−plasma forms clots with compact structure as determined by the reduced dissipation values 73.2 ± 34.0 vs. 155 ± 53.8 (n = 7–5, P = 0.009) compared with Wt plasma. These data suggest that CD44-deficiency promotes blood clots with more densly packed fibrin and less elastic composition. Reduced CD44 expression may therefore counteract the thrombogenicity of Wt plasma. In conclusion, contrary to earlier results in ApoE−/− mice, these studies suggest that CD44 does not influence atherogenesis in LDLr−/− mice. However, absence of CD44 reduces antithrombin activity which contributes to an altered extrinsic clotting cascade, giving insight into the role of CD44 in molecular events governing plaque disruptions.