title: Effects of DNA damage in smooth muscle cells in atherosclerosis.
abstract: BACKGROUND
  DNA damage and the DNA damage response have been identified in human atherosclerosis, including in vascular smooth muscle cells (VSMCs). However, although double-stranded breaks (DSBs) are hypothesized to promote plaque progression and instability, in part, by promoting cell senescence, apoptosis, and inflammation, the direct effects of DSBs in VSMCs seen in atherogenesis are unknown.
  
  
  OBJECTIVE
  To determine the presence and effect of endogenous levels of DSBs in VSMCs on atherosclerosis.
  
  
  RESULTS
  Human atherosclerotic plaque VSMCs showed increased expression of multiple DNA damage response proteins in vitro and in vivo, particularly the MRE11/RAD50/NBS1 complex that senses DSB repair. Oxidative stress-induced DSBs were increased in plaque VSMCs, but DSB repair was maintained. To determine the effect of DSBs on atherosclerosis, we generated 2 novel transgenic mice lines expressing NBS1 or C-terminal deleted NBS1 only in VSMCs, and crossed them with apolipoprotein E(-/-) mice. SM22α-NBS1/apolipoprotein E(-/-) VSMCs showed enhanced DSB repair and decreased growth arrest and apoptosis, whereas SM22α-(ΔC)NBS1/apolipoprotein E(-/-) VSMCs showed reduced DSB repair and increased growth arrest and apoptosis. Accelerating or retarding DSB repair did not affect atherosclerosis extent or composition. However, VSMC DNA damage reduced relative fibrous cap areas, whereas accelerating DSB repair increased cap area and VSMC content.
  
  
  CONCLUSIONS
  Human atherosclerotic plaque VSMCs show increased DNA damage, including DSBs and DNA damage response activation. VSMC DNA damage has minimal effects on atherogenesis, but alters plaque phenotype inhibiting fibrous cap areas in advanced lesions. Inhibiting DNA damage in atherosclerosis may be a novel target to promote plaque stability.
authors.affiliation: From the Division of Cardiovascular Medicine (K.G., S.K., N.F., J.H., L.B., J.M., M.B.) and Department of Biochemistry (T.L.), Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Kelly
authors.initials: K
authors.lastname: Gray
authors.affiliation: From the Division of Cardiovascular Medicine (K.G., S.K., N.F., J.H., L.B., J.M., M.B.) and Department of Biochemistry (T.L.), Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Sheetal
authors.initials: S
authors.lastname: Kumar
authors.affiliation: From the Division of Cardiovascular Medicine (K.G., S.K., N.F., J.H., L.B., J.M., M.B.) and Department of Biochemistry (T.L.), Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Nichola
authors.initials: N
authors.lastname: Figg
authors.affiliation: From the Division of Cardiovascular Medicine (K.G., S.K., N.F., J.H., L.B., J.M., M.B.) and Department of Biochemistry (T.L.), Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Harrison
authors.affiliation: From the Division of Cardiovascular Medicine (K.G., S.K., N.F., J.H., L.B., J.M., M.B.) and Department of Biochemistry (T.L.), Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Lauren
authors.initials: L
authors.lastname: Baker
authors.affiliation: From the Division of Cardiovascular Medicine (K.G., S.K., N.F., J.H., L.B., J.M., M.B.) and Department of Biochemistry (T.L.), Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Mercer
authors.affiliation: From the Division of Cardiovascular Medicine (K.G., S.K., N.F., J.H., L.B., J.M., M.B.) and Department of Biochemistry (T.L.), Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Trevor
authors.initials: T
authors.lastname: Littlewood
authors.affiliation: From the Division of Cardiovascular Medicine (K.G., S.K., N.F., J.H., L.B., J.M., M.B.) and Department of Biochemistry (T.L.), Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom. mrb@mole.bio.cam.ac.uk.
authors.forename: Martin
authors.initials: M
authors.lastname: Bennett
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D016122:Brachiocephalic Trunk / Q000473:pathology; D002339:Carotid Arteries / Q000166:cytology; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000096:biosynthesis / Q000235:genetics; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D001057:Apolipoproteins E; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; C112156:NBN protein, human; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; C051615:transgelin; D045643:DNA Repair Enzymes
keywords: DNA damage; apoptosis; atherosclerosis