Overexpression of the cell cycle inhibitor p16INK4a promotes a prothrombotic phenotype following vascular injury in mice.
نویسندگان
چکیده
OBJECTIVE Age-associated cellular senescence is thought to promote vascular dysfunction. p16(INK4a) is a cell cycle inhibitor that promotes senescence and is upregulated during normal aging. In this study, we examine the contribution of p16(INK4a) overexpression to venous thrombosis. METHODS AND RESULTS Mice overexpressing p16(INK4a) were studied with 4 different vascular injury models: (1) ferric chloride (FeCl(3)) and (2) Rose Bengal to induce saphenous vein thrombus formation; (3) FeCl(3) and vascular ligation to examine thrombus resolution; and (4) lipopolysaccharide administration to initiate inflammation-induced vascular dysfunction. p16(INK4a) transgenic mice had accelerated occlusion times (13.1 ± 0.4 minutes) compared with normal controls (19.7 ± 1.1 minutes) in the FeCl(3) model and 12.7 ± 2.0 and 18.6 ± 1.9 minutes, respectively in the Rose Bengal model. Moreover, overexpression of p16(INK4a) delayed thrombus resolution compared with normal controls. In response to lipopolysaccharide treatment, the p16(INK4a) transgenic mice showed enhanced thrombin generation in plasma-based calibrated automated thrombography assays. Finally, bone marrow transplantation studies suggested increased p16(INK4a) expression in hematopoietic cells contributes to thrombosis, demonstrating a role for p16(INK4a) expression in venous thrombosis. CONCLUSIONS Venous thrombosis is augmented by overexpression of the cellular senescence protein p16(INK4a).
منابع مشابه
Overexpression of the Cell Cycle Inhibitor p16 Promotes a Prothrombotic Phenotype Following Vascular Injury in Mice
controls (19.7 1.1 minutes) in the FeCl3 model and 12.7 2.0 and 18.6 1.9 minutes, respectively in the Rose Bengal model. Moreover, overexpression of p16 delayed thrombus resolution compared with normal controls. In response to lipopolysaccharide treatment, the p16 transgenic mice showed enhanced thrombin generation in plasma-based calibrated automated thrombography assays. Finally, bone marrow ...
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ورودعنوان ژورنال:
- Arteriosclerosis, thrombosis, and vascular biology
دوره 31 4 شماره
صفحات -
تاریخ انتشار 2011