Effects of the Factor Xa Inhibitor, Fondaparinux, on the Stability of Atherosclerotic Lesions in Apolipoprotein E-Deficient Mice

Abstract

Background:Atherosclerosis is a progressive inflammatory disease that can lead to sudden cardiac events by plaque rupture and subsequent thrombosis. Factor Xa (FXa) not only occupies a crucial position in the coagulation cascade responsible for thrombin generation, but also has pro-inflammatory effects. The hypothesis that Fondaparinux, the selective FXa inhibitor, attenuates plaque progression and promotes stability of atherosclerotic lesions was assessed.Methods and Results:Fondaparinux (5 mg/kg body weight/day) or 0.9% saline was intraperitoneally administered for 4 weeks to apolipoprotein E-deficient mice (n=12 per group) with established atherosclerotic lesions in the innominate arteries. Fondaparinux did not remarkably decrease the progression of atherosclerosis development in apolipoprotein E-deficient mice, but increased the thickness of fibrous cap (P=0.049) and decreased the ratio of necrotic core (P=0.001) significantly. Moreover, Fondaparinux reduced the staining against Mac-2 (P=0.017), α-SMA (P=0.002), protease-activated receptor (PAR)-1 (P=0.001), PAR-2 (P=0.003), CD-31 (P=0.024), MMP-9 (P=0.000), MMP-13(P=0.011), VCAM-1 (P=0.041) and the mRNA expression of inflammatory mediators (P<0.05) significantly, such as interleukin (IL)-6, MCP-1, IFN-γ, TNF-α, IL-10 and Egr-1.Conclusions:Fondaparinux, the selective FXa inhibitor, can promote the stability of atherosclerotic lesions in apolipoprotein E-deficient mice, possibly through inhibiting expression of the inflammatory mediators in plaque and reduced synthesis of MMP-9 and MMP-13.