Overexpression of the Cell Cycle Inhibitor p16INK4a Promotes a Prothrombotic Phenotype Following Vascular Injury in Mice

被引:22
作者
Cardenas, Jessica C.
Owens, A. Phillip, III [2 ,3 ]
Krishnamurthy, Janakiraman [3 ,4 ,5 ]
Sharpless, Norman E. [3 ,4 ,5 ]
Whinna, Herbert C. [2 ]
Church, Frank C. [1 ,2 ,3 ]
机构
[1] Univ N Carolina, Dept Pathol & Lab Med, Div Hematol & Oncol Med, Sch Med, Chapel Hill, NC 27599 USA
[2] Univ N Carolina, Sch Med, McAllister Heart Inst, Chapel Hill, NC 27599 USA
[3] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USA
[4] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC 27599 USA
[5] Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
基金
美国国家卫生研究院;
关键词
aging; coagulation; pathology; thrombosis; PLASMINOGEN-ACTIVATOR INHIBITOR-1; DEEP-VEIN THROMBOSIS; IN-VIVO; VENOUS THROMBOSIS; TISSUE FACTOR; ARTERIAL THROMBOSIS; COAGULATION ACTIVATION; ENDOTHELIAL-CELLS; ENDOTOXEMIC MICE; MURINE MODELS;
D O I
10.1161/ATVBAHA.110.221721
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
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 (FeCl3) and (2) Rose Bengal to induce saphenous vein thrombus formation; (3) FeCl3 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 FeCl3 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. Conclusion-Venous thrombosis is augmented by overexpression of the cellular senescence protein p16(INK4a). (Arterioscler Thromb Vasc Biol. 2011;31:827-833.)
引用
收藏
页码:827 / U239
页数:19
相关论文
共 57 条
[1]
Healing and Hurting: Molecular Mechanisms, Functions, and Pathologies of Cellular Senescence [J].
Adams, Peter D. .
MOLECULAR CELL, 2009, 36 (01) :2-14
[2]
Expression of Linear and Novel Circular Forms of an INK4/ARF-Associated Non-Coding RNA Correlates with Atherosclerosis Risk [J].
Burd, Christin E. ;
Jeck, William R. ;
Liu, Yan ;
Sanoff, Hanna K. ;
Wang, Zefeng ;
Sharpless, Norman E. .
PLOS GENETICS, 2010, 6 (12) :1-15
[3]
Cellular senescence: when bad things happen to good cells [J].
Campisi, Judith ;
di Fagagna, Fabrizio d'Adda .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2007, 8 (09) :729-740
[4]
EPIDEMIOLOGY OF VENOUS THROMBOEMBOLISM [J].
COON, WW .
ANNALS OF SURGERY, 1977, 186 (02) :149-164
[5]
Dimri G. P., 2004, SCI AGING KNOWLEDGE, V2004, ppe40
[6]
Glycoprotein VI-dependent and -independent pathways of thrombus formation in vivo [J].
Dubois, Christophe ;
Panicot-Dubois, Laurence ;
Merrill-Skoloff, Glenn ;
Furie, Bruce ;
Furie, Barbara C. .
BLOOD, 2006, 107 (10) :3902-3906
[7]
Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene [J].
Eitzman, DT ;
McCoy, RD ;
Zheng, XX ;
Fay, WP ;
Shen, TL ;
Ginsburg, D ;
Simon, RH .
JOURNAL OF CLINICAL INVESTIGATION, 1996, 97 (01) :232-237
[8]
Plasminogen activator inhibitor-1 and vitronectin promote vascular thrombosis in mice [J].
Eitzman, DT ;
Westrick, RJ ;
Nabel, EG ;
Ginsburg, D .
BLOOD, 2000, 95 (02) :577-580
[9]
Cellular senescence in vivo: Its relevance in ageing and cardiovascular disease [J].
Erusalimsky, JD ;
Kurz, DJ .
EXPERIMENTAL GERONTOLOGY, 2005, 40 (8-9) :634-642
[10]
Mechanisms of endothelial senescence [J].
Erusalimsky, Jorge D. ;
Skene, Chris .
EXPERIMENTAL PHYSIOLOGY, 2009, 94 (03) :299-304