title: The methyl xanthine caffeine inhibits DNA damage signaling and reactive species and reduces atherosclerosis in ApoE(-/-) mice.
abstract: OBJECTIVE
  Caffeine remains one of the most widely consumed drugs in the world. Caffeine has multiple actions, including inhibition of the DNA damage response, and its metabolites, 1-methylxanthine and 1-methyluric acid, are potent antioxidants. Combined, these properties can exert direct effects on cell proliferation, cell death, inflammation, and DNA repair, all important processes that occur in atherosclerosis.
  
  
  RESULTS
  We first examined the effects of caffeine on mouse vascular smooth muscle cells. Caffeine inhibited activation of the DNA damage response regulator ataxia telangiectasia mutated protein and its downstream targets. Caffeine delayed DNA repair, had a concentration-dependent effect on cell proliferation, and protected against apoptosis. In vitro caffeine reduced oxygen consumption and decreased generation of reactive oxygen species. In vivo caffeine reduced DDR activation in vascular and nonvascular tissues, reduced reactive nitrogen species and serum levels of the DNA adduct 8-oxo-guanine, and inhibited atherogenesis in fat-fed ApoE(-/-) mice. Reduction in atherosclerosis was independent of the effects on blood pressure and serum lipids but associated with reduced cell proliferation and ataxia telangiectasia mutated protein activation.
  
  
  CONCLUSIONS
  The Methyl Xanthine caffeine inhibits the DNA damage response in vitro and in vivo, regulates both cell proliferation and apoptosis after DNA damage, inhibits reactive species, and reduces atherogenesis in ApoE(-/-) mice.
authors.affiliation: Division of Cardiovascular Medicine, University of Cambridge, ACCI, Level 6, Box 110, Addenbrooke's Hospital, Cambridge, CB2 2QQ, United Kingdom. jm317@cam.ac.uk
authors.forename: John R
authors.initials: JR
authors.lastname: Mercer
authors.forename: Kelly
authors.initials: K
authors.lastname: Gray
authors.forename: Nichola
authors.initials: N
authors.lastname: Figg
authors.forename: Sheetal
authors.initials: S
authors.lastname: Kumar
authors.forename: Martin R
authors.initials: MR
authors.lastname: Bennett
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D002110:Caffeine / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018736:DNA Adducts / Q000097:blood; D004249:DNA Damage / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014970:Xanthines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001057:Apolipoproteins E; D018736:DNA Adducts; D017382:Reactive Oxygen Species; D014970:Xanthines; C008514:methylxanthine; D002110:Caffeine