Abstract 19565: Genetically Imposed Hypocoagulability Inhibits Atherogenesis and Promotes Plaque Stability
Introduction: Although the generation of thrombin is pivotal for hemostasis, thrombin may also be a potent mediator of cellular effects. By activating protease activated receptors, thrombin elicits diverse cellular effects, including on migration and profileration of VSMC that may be relevant to atherosclerosis. While pharmacological inhibition of thrombin attenuated atherosclerosis burden in mice, the effect of genetically altered levels of thrombin generation is unknown.
Hypothesis: Heterozygosity for the prothrombin gene reduces the level of thrombin generation in blood, inhibits atherogenesis and promotes plaque stability.
Methods: We generated transgenic mice with a diminished coagulant phenotype (FII-/WT:ApoE−/− — prothrombin heterozygotes have a ∼50% reduced thrombin generation) and compared these to control mice. Two atherosclerosis models were studied: a spontaneous course model in which animals were fed a regular chow for 35 weeks and a cuff carotid model. All vessels were processed for extensive morphological and quantitative analysis. Data are presented as mean ± SEM.
Results and Conclusions: Plasma prothrombin, FVII, and thrombin generation levels were pronouncedly decreased in FII-/WT:ApoE−/− mice compared to controls. FII-/WT:ApoE−/− demonstrated significantly reduced atherosclerotic plaque size (72.51 ± 8,88 x103 μm2) compared to controls (128.44 ± 16,67 x103 μm2) (n=10 per group; p=0.0089). FII-/WT:ApoE−/− lesions also showed a more stable phenotype, characterized by abundant collagen and VSMC (fibrous caps), whereas necrotic cores were either small or absent and infiltration of monocytes was significantly diminished. TUNEL staining revealed that prothrombin heterozygotes show significantly less apoptosis than the plaques of control animals. In conclusion, these data support the hypothesis that variations in endogenous thrombin generation may be relevant to the risk of atherothrombosis.
- © 2010 by American Heart Association, Inc.