title: Vascular Smooth Muscle Cell Senescence Promotes Atherosclerosis and Features of Plaque Vulnerability.
abstract: BACKGROUND
  Although vascular smooth muscle cell (VSMC) proliferation is implicated in atherogenesis, VSMCs in advanced plaques and cultured from plaques show evidence of VSMC senescence and DNA damage. In particular, plaque VSMCs show shortening of telomeres, which can directly induce senescence. Senescence can have multiple effects on plaque development and morphology; however, the consequences of VSMC senescence or the mechanisms underlying VSMC senescence in atherosclerosis are mostly unknown.
  
  
  RESULTS
  We examined the expression of proteins that protect telomeres in VSMCs derived from human plaques and normal vessels. Plaque VSMCs showed reduced expression and telomere binding of telomeric repeat-binding factor-2 (TRF2), associated with increased DNA damage. TRF2 expression was regulated by p53-dependent degradation of the TRF2 protein. To examine the functional consequences of loss of TRF2, we expressed TRF2 or a TRF2 functional mutant (T188A) as either gain- or loss-of-function studies in vitro and in apolipoprotein E(-/-) mice. TRF2 overexpression bypassed senescence, reduced DNA damage, and accelerated DNA repair, whereas TRF2(188A) showed opposite effects. Transgenic mice expressing VSMC-specific TRF2(T188A) showed increased atherosclerosis and necrotic core formation in vivo, whereas VSMC-specific TRF2 increased the relative fibrous cap and decreased necrotic core areas. TRF2 protected against atherosclerosis independent of secretion of senescence-associated cytokines.
  
  
  CONCLUSIONS
  We conclude that plaque VSMC senescence in atherosclerosis is associated with loss of TRF2. VSMC senes cence promotes both atherosclerosis and features of plaque vulnerability, identifying prevention of senescence as a potential target for intervention.
authors.affiliation: From Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Wang
authors.affiliation: From Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Uryga
authors.affiliation: From Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Johannes
authors.initials: J
authors.lastname: Reinhold
authors.affiliation: From Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Nichola
authors.initials: N
authors.lastname: Figg
authors.affiliation: From Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Lauren
authors.initials: L
authors.lastname: Baker
authors.affiliation: From Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Finigan
authors.affiliation: From Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Kelly
authors.initials: K
authors.lastname: Gray
authors.affiliation: From Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Sheetal
authors.initials: S
authors.lastname: Kumar
authors.affiliation: From Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Murray
authors.initials: M
authors.lastname: Clarke
authors.affiliation: From Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom. mrb@mole.bio.cam.ac.uk.
authors.forename: Martin
authors.initials: M
authors.lastname: Bennett
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000378:metabolism* / Q000473:pathology
keywords: aging; atherosclerosis; muscle, smooth; vascular diseases