title: Mitochondrial DNA damage can promote atherosclerosis independently of reactive oxygen species through effects on smooth muscle cells and monocytes and correlates with higher-risk plaques in humans.
abstract: BACKGROUND
  Mitochondrial DNA (mtDNA) damage occurs in both circulating cells and the vessel wall in human atherosclerosis. However, it is unclear whether mtDNA damage directly promotes atherogenesis or is a consequence of tissue damage, which cell types are involved, and whether its effects are mediated only through reactive oxygen species.
  
  
  RESULTS
  mtDNA damage occurred early in the vessel wall in apolipoprotein E-null (ApoE(-/-)) mice, before significant atherosclerosis developed. mtDNA defects were also identified in circulating monocytes and liver and were associated with mitochondrial dysfunction. To determine whether mtDNA damage directly promotes atherosclerosis, we studied ApoE(-/-) mice deficient for mitochondrial polymerase-γ proofreading activity (polG(-/-)/ApoE(-/-)). polG(-/-)/ApoE(-/-) mice showed extensive mtDNA damage and defects in oxidative phosphorylation but no increase in reactive oxygen species. polG(-/-)/ApoE(-/-) mice showed increased atherosclerosis, associated with impaired proliferation and apoptosis of vascular smooth muscle cells, and hyperlipidemia. Transplantation with polG(-/-)/ApoE(-/-) bone marrow increased the features of plaque vulnerability, and polG(-/-)/ApoE(-/-) monocytes showed increased apoptosis and inflammatory cytokine release. To examine mtDNA damage in human atherosclerosis, we assessed mtDNA adducts in plaques and in leukocytes from patients who had undergone virtual histology intravascular ultrasound characterization of coronary plaques. Human atherosclerotic plaques showed increased mtDNA damage compared with normal vessels; in contrast, leukocyte mtDNA damage was associated with higher-risk plaques but not plaque burden.
  
  
  CONCLUSIONS
  We show that mtDNA damage in vessel wall and circulating cells is widespread and causative and indicates higher risk in atherosclerosis. Protection against mtDNA damage and improvement of mitochondrial function are potential areas for new therapeutics.
authors.affiliation: Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Centre for Clinical Investigation, P.O. Box 110, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Yu
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Calvert
authors.forename: John R
authors.initials: JR
authors.lastname: Mercer
authors.forename: James
authors.initials: J
authors.lastname: Harrison
authors.forename: Lauren
authors.initials: L
authors.lastname: Baker
authors.forename: Nichola L
authors.initials: NL
authors.lastname: Figg
authors.forename: Sheetal
authors.initials: S
authors.lastname: Kumar
authors.forename: Julie C
authors.initials: JC
authors.lastname: Wang
authors.forename: Liam A
authors.initials: LA
authors.lastname: Hurst
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Obaid
authors.forename: Angela
authors.initials: A
authors.lastname: Logan
authors.forename: Nick E J
authors.initials: NE
authors.lastname: West
authors.forename: Murray C H
authors.initials: MC
authors.lastname: Clarke
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: Martin R
authors.initials: MR
authors.lastname: Bennett
mesh_terms: D050154:Adiposity; D000328:Adult; D000368:Aged; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D018736:DNA Adducts / Q000032:analysis; D004249:DNA Damage; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000737:chemistry*; D004259:DNA-Directed DNA Polymerase / Q000172:deficiency / Q000235:genetics; D004579:Electron Transport; D005260:Female; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D008928:Mitochondria / Q000737:chemistry / Q000473:pathology* / Q000502:physiology; D009000:Monocytes / Q000378:metabolism / Q000473:pathology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000473:pathology*; D010101:Oxygen Consumption; D058226:Plaque, Atherosclerotic / Q000473:pathology*; D011828:Radiation Chimera; D017382:Reactive Oxygen Species; D012306:Risk
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D018736:DNA Adducts; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C498803:Polg protein, mouse
keywords: apoptosis; atherosclerosis; free radicals