title: Loss of CDKN2B promotes p53-dependent smooth muscle cell apoptosis and aneurysm formation.
abstract: OBJECTIVE
  Genomewide association studies have implicated allelic variation at 9p21.3 in multiple forms of vascular disease, including atherosclerotic coronary heart disease and abdominal aortic aneurysm. As for other genes at 9p21.3, human expression quantitative trait locus studies have associated expression of the tumor suppressor gene CDKN2B with the risk haplotype, but its potential role in vascular pathobiology remains unclear.
  
  
  RESULTS
  Here we used vascular injury models and found that Cdkn2b knockout mice displayed the expected increase in proliferation after injury, but developed reduced neointimal lesions and larger aortic aneurysms. In situ and in vitro studies suggested that these effects were attributable to increased smooth muscle cell apoptosis. Adoptive bone marrow transplant studies confirmed that the observed effects of Cdkn2b were mediated through intrinsic vascular cells and were not dependent on bone marrow-derived inflammatory cells. Mechanistic studies suggested that the observed increase in apoptosis was attributable to a reduction in MDM2 and an increase in p53 signaling, possibly due in part to compensation by other genes at the 9p21.3 locus. Dual inhibition of both Cdkn2b and p53 led to a reversal of the vascular phenotype in each model.
  
  
  CONCLUSIONS
  These results suggest that reduced CDKN2B expression and increased smooth muscle cell apoptosis may be one mechanism underlying the 9p21.3 association with aneurysmal disease.
authors.affiliation: Department of Surgery, Stanford University, 300 Pasteur Dr, Stanford, CA 94305, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Leeper
authors.forename: Azad
authors.initials: A
authors.lastname: Raiesdana
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kojima
authors.forename: Ramendra K
authors.initials: RK
authors.lastname: Kundu
authors.forename: Henry
authors.initials: H
authors.lastname: Cheng
authors.forename: Lars
authors.initials: L
authors.lastname: Maegdefessel
authors.forename: Ryuji
authors.initials: R
authors.lastname: Toh
authors.forename: G-One
authors.initials: GO
authors.lastname: Ahn
authors.forename: Ziad A
authors.initials: ZA
authors.lastname: Ali
authors.forename: D Ryan
authors.initials: DR
authors.lastname: Anderson
authors.forename: Clint L
authors.initials: CL
authors.lastname: Miller
authors.forename: Scott C
authors.initials: SC
authors.lastname: Roberts
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Spin
authors.forename: Patricia E
authors.initials: PE
authors.lastname: de Almeida
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
authors.forename: Baohui
authors.initials: B
authors.lastname: Xu
authors.forename: Karen
authors.initials: K
authors.lastname: Cheng
authors.forename: Maximilian
authors.initials: M
authors.lastname: Quertermous
authors.forename: Soumajit
authors.initials: S
authors.lastname: Kundu
authors.forename: Kim E
authors.initials: KE
authors.lastname: Kortekaas
authors.forename: Erica
authors.initials: E
authors.lastname: Berzin
authors.forename: Kelly P
authors.initials: KP
authors.lastname: Downing
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Dalman
authors.forename: Philip S
authors.initials: PS
authors.lastname: Tsao
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Gary K
authors.initials: GK
authors.lastname: Owens
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D017209:Apoptosis / Q000187:drug effects; D052160:Benzothiazoles / Q000494:pharmacology; D016026:Bone Marrow Transplantation; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002340:Carotid Artery Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016022:Case-Control Studies; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058426:Neointima; D010196:Pancreatic Elastase; D010641:Phenotype; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055815:Young Adult
chemical_list: D052160:Benzothiazoles; C493966:CDKN2B protein, human; C493968:Cdkn2b protein, mouse; D050762:Cyclin-Dependent Kinase Inhibitor p15; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D010196:Pancreatic Elastase