title: Overexpression of the cell cycle inhibitor p16INK4a promotes a prothrombotic phenotype following vascular injury in mice.
abstract: 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.
  
  
  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).
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina-Chapel Hill, NC 27599-7035, USA.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Cardenas
authors.forename: A Phillip
authors.initials: AP
authors.lastname: Owens
authors.forename: Janakiraman
authors.initials: J
authors.lastname: Krishnamurthy
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Whinna
authors.forename: Frank C
authors.initials: FC
authors.lastname: Church
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000235:genetics; D001780:Blood Coagulation Tests; D016026:Bone Marrow Transplantation; D002712:Chlorides; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005290:Ferric Compounds; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D008026:Ligation; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D012395:Rose Bengal; D013997:Time Factors; D015854:Up-Regulation; D057772:Vascular System Injuries / Q000097:blood* / Q000209:etiology / Q000235:genetics; D020246:Venous Thrombosis / Q000097:blood* / Q000209:etiology / Q000235:genetics
chemical_list: C417743:Cdkn2a protein, mouse; D002712:Chlorides; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005290:Ferric Compounds; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D012395:Rose Bengal; C024555:ferric chloride