title: Deletion of chromosome 9p21 noncoding cardiovascular risk interval in mice alters Smad2 signaling and promotes vascular aneurysm.
abstract: BACKGROUND
  Vascular aneurysm is an abnormal local dilatation of an artery that can lead to vessel rupture and sudden death. The only treatment involves surgical or endovascular repair or exclusion. There is currently no approved medical therapy for this condition. Recent data established a strong association between genetic variants in the 9p21 chromosomal region in humans and the presence of cardiovascular diseases, including aneurysms. However, the mechanisms linking this 9p21 DNA variant to cardiovascular risk are still unknown.
  
  
  RESULTS
  Here, we show that deletion of the orthologous 70-kb noncoding interval on mouse chromosome 4 (chr4(Δ70kb/Δ70kb) mice) is associated with reduced aortic expression of cyclin-dependent kinase inhibitor genes p19Arf and p15Inkb. Vascular smooth muscle cells from chr4(Δ70kb/Δ70kb) mice show reduced transforming growth factor-β-dependent canonical Smad2 signaling but increased cyclin-dependent kinase-dependent Smad2 phosphorylation at linker sites, a phenotype previously associated with tumor growth and consistent with the mechanistic link between reduced canonical transforming growth factor-β signaling and susceptibility to vascular diseases. We also show that targeted deletion of the 9p21 risk interval promotes susceptibility to aneurysm development and rupture when mice are subjected to a validated model of aneurysm formation. The vascular disease of chr4(Δ70kb/Δ70kb) mice is prevented by treatment with a cyclin-dependent kinase inhibitor.
  
  
  CONCLUSIONS
  The results establish a direct mechanistic link between 9p21 noncoding risk interval and susceptibility to aneurysm and may have important implications for the understanding and treatment of vascular diseases.
authors.affiliation: From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Université Paris-Descartes, Paris, France (J.V., Z.M.).
authors.forename: Céline
authors.initials: C
authors.lastname: Loinard
authors.affiliation: From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Université Paris-Descartes, Paris, France (J.V., Z.M.).
authors.forename: Gemma
authors.initials: G
authors.lastname: Basatemur
authors.affiliation: From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Université Paris-Descartes, Paris, France (J.V., Z.M.).
authors.forename: Leanne
authors.initials: L
authors.lastname: Masters
authors.affiliation: From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Université Paris-Descartes, Paris, France (J.V., Z.M.).
authors.forename: Lauren
authors.initials: L
authors.lastname: Baker
authors.affiliation: From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Université Paris-Descartes, Paris, France (J.V., Z.M.).
authors.forename: James
authors.initials: J
authors.lastname: Harrison
authors.affiliation: From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Université Paris-Descartes, Paris, France (J.V., Z.M.).
authors.forename: Nichola
authors.initials: N
authors.lastname: Figg
authors.affiliation: From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Université Paris-Descartes, Paris, France (J.V., Z.M.).
authors.forename: José
authors.initials: J
authors.lastname: Vilar
authors.affiliation: From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Université Paris-Descartes, Paris, France (J.V., Z.M.).
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Sage
authors.affiliation: From the Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom (C.L., G.B., L.M., L.B., J.H., N.F., A.P.S., Z.M.); and Institut National de la Santé et de la Recherche Médicale (Inserm), Unit 970, Paris Cardiovascular Research Center, Université Paris-Descartes, Paris, France (J.V., Z.M.). zm255@medchl.cam.ac.uk.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Mallat
mesh_terms: D000783:Aneurysm / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D000818:Animals; D002478:Cells, Cultured; D002875:Chromosomes / Q000235:genetics* / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000172:deficiency / Q000235:genetics; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects; D053208:Kaplan-Meier Estimate; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D050764:Cyclin-Dependent Kinase Inhibitor p19; D005419:Flavonoids; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; C077990:alvocidib; D053508:Matrix Metalloproteinase 12
keywords: aneurysm; genetics; models, animal; myocytes, smooth muscle