title: Smoking cessation reverses DNA double-strand breaks in human mononuclear cells.
abstract: OBJECTIVE
  Cigarette smoking is a major risk factor for atherosclerotic cardiovascular disease, which is responsible for a significant proportion of smoking-related deaths. However, the precise mechanism whereby smoking induces this pathology has not been fully delineated. Based on observation of DNA double-strand breaks (DSBs), the most harmful type of DNA damage, in atherosclerotic lesions, we hypothesized that there is a direct association between smoking and DSBs. The goal of this study was to investigate whether smoking induces DSBs and smoking cessation reverses DSBs in vivo through examination of peripheral mononuclear cells (MNCs).
  
  
  RESULTS
  Immunoreactivity of oxidative modification of DNA and DSBs were increased in human atherosclerotic lesions but not in the adjacent normal area. DSBs in human MNCs isolated from the blood of volunteers can be detected as cytologically visible "foci" using an antibody against the phosphorylated form of the histone H2AX (γ-H2AX). Young healthy active smokers (n = 15) showed increased γ-H2AX foci number when compared with non-smokers (n = 12) (foci number/cell: median, 0.37/cell; interquartile range [IQR], 0.31-0.58 vs. 4.36/cell; IQR, 3.09-7.39, p<0.0001). Smoking cessation for 1 month reduced the γ-H2AX foci number (median, 4.44/cell; IQR, 4.36-5.24 to 0.28/cell; IQR, 0.12-0.53, p<0.05). A positive correlation was noted between γ-H2AX foci number and exhaled carbon monoxide levels (r = 0.75, p<0.01).
  
  
  CONCLUSIONS
  Smoking induces DSBs in human MNCs in vivo, and importantly, smoking cessation for 1 month resulted in a decrease in DSBs to a level comparable to that seen in non-smokers. These data reinforce the notion that the cigarette smoking induces DSBs and highlight the importance of smoking cessation.
authors.affiliation: Department of Cardiovascular Physiology and Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Ishida
authors.affiliation: Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Department of Cellular Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tashiro
authors.affiliation: Department of Cardiovascular Physiology and Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Uchida
authors.affiliation: Department of Cardiovascular Physiology and Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Chiemi
authors.initials: C
authors.lastname: Sakai
authors.affiliation: Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Hironobe
authors.affiliation: Department of Cardiovascular Physiology and Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Miura
authors.affiliation: Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Arihiro
authors.affiliation: Department of Gastroenterology and Metabolism, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
authors.affiliation: Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Kihara
authors.affiliation: Department of Cardiovascular Physiology and Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Yoshizumi
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism; D006656:Protamine Kinase / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects; D016540:Smoking Cessation; D014026:Nicotiana / Q000009:adverse effects; D055815:Young Adult
chemical_list: C468783:H2AX protein, human; D006657:Histones; D012906:Smoke; D006861:Hydrogen Peroxide; D006656:Protamine Kinase
references.citation: Circulation. 2003 Nov 4;108(18):2264-9
references.pmid: 14557365
references.citation: Circ Res. 1998 Jan 9-23;82(1):7-12
references.pmid: 9440699
references.citation: Nat Genet. 2001 Mar;27(3):247-54
references.pmid: 11242102
references.citation: Mutat Res. 2009 Aug;678(1):43-52
references.pmid: 19591958
references.citation: Arterioscler Thromb Vasc Biol. 2009 Feb;29(2):169-72
references.pmid: 18988889
references.citation: Cell Cycle. 2010 Jun 1;9(11):2170-6
references.pmid: 20404482
references.citation: Chest. 2000 Mar;117(3):758-63
references.pmid: 10713003
references.citation: Hum Pathol. 2014 Jan;45(1):17-26
references.pmid: 24125744
references.citation: Nat Cell Biol. 2011 Oct 03;13(10):1161-9
references.pmid: 21968989
references.citation: Int J Environ Res Public Health. 2009 Mar;6(3):874-88
references.pmid: 19440419
references.citation: Eur Heart J. 1992 Feb;13(2):166-70
references.pmid: 1313369
references.citation: Mutat Res. 1999 Feb 19;439(2):249-57
references.pmid: 10023075
references.citation: Thorax. 1981 May;36(5):366-9
references.pmid: 7314006
references.citation: Clin Interv Aging. 2008;3(3):431-44
references.pmid: 18982914
references.citation: Cell Cycle. 2004 Aug;3(8):1062-8
references.pmid: 15254392
references.citation: Circ Res. 2008 Sep 26;103(7):717-25
references.pmid: 18723444
references.citation: Carcinogenesis. 2000 Feb;21(2):183-7
references.pmid: 10657956
references.citation: Crit Rev Toxicol. 1997 Mar;27(2):155-74
references.pmid: 9099517
references.citation: Fundam Clin Pharmacol. 2011 Aug;25(4):425-42
references.pmid: 20698892
references.citation: Cell Metab. 2007 Sep;6(3):164-79
references.pmid: 17767904
references.citation: Circulation. 2006 Aug 29;114(9):953-60
references.pmid: 16908765
references.citation: Circ Res. 2012 Jul 6;111(2):245-59
references.pmid: 22773427
references.citation: Am J Physiol. 1998 Sep;275(3):H1040-5
references.pmid: 9724311
references.citation: DNA Repair (Amst). 2008 Jan 1;7(1):48-56
references.pmid: 17827074
references.citation: Carcinogenesis. 1999 Mar;20(3):437-44
references.pmid: 10190559
references.citation: Biochemistry (Mosc). 2012 May;77(5):524-31
references.pmid: 22813594
references.citation: Am J Cardiol. 2008 Nov 15;102(10):1421-4
references.pmid: 18993167
references.citation: Cancer Res. 1996 Jun 1;56(11):2546-9
references.pmid: 8653695
references.citation: Nat Cell Biol. 2009 Aug;11(8):973-9
references.pmid: 19597488
references.citation: DNA Repair (Amst). 2010 Dec 10;9(12):1219-28
references.pmid: 21035408
references.citation: Cancer Lett. 2006 May 8;236(1):24-31
references.pmid: 15967573
references.citation: Oxid Med Cell Longev. 2013;2013:189129
references.pmid: 24381713
references.citation: Mutat Res. 2009 Feb 19;673(1):3-8
references.pmid: 19100859
references.citation: Nat Med. 2006 Sep;12(9):1075-80
references.pmid: 16892061
references.citation: Nucleic Acids Res. 2008 Oct;36(17):5678-94
references.pmid: 18772227
references.citation: N Engl J Med. 2013 Mar 14;368(11):987-98
references.pmid: 23484825