title: Ogg1-Dependent DNA Repair Regulates NLRP3 Inflammasome and Prevents Atherosclerosis.
abstract: BACKGROUND
  Activation of NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome-mediating interleukin (IL)-1β secretion has emerged as an important component of inflammatory processes in atherosclerosis. Mitochondrial DNA (mtDNA) damage is detrimental in atherosclerosis, and mitochondria are central regulators of the nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3 inflammasome. Human atherosclerotic plaques express increased mtDNA damage. The major DNA glycosylase, 8-oxoguanine glycosylase (OGG1), is responsible for removing the most abundant form of oxidative DNA damage.
  
  
  OBJECTIVE
  To test the role of OGG1 in the development of atherosclerosis in mouse.
  
  
  RESULTS
  We observed that Ogg1 expression decreases over time in atherosclerotic lesion macrophages of low-density lipoprotein receptor (Ldlr) knockout mice fed a Western diet. Ogg1(-/-)Ldlr(-/-) mice fed a Western diet resulted in an increase in plaque size and lipid content. We found increased oxidized mtDNA, inflammasome activation, and apoptosis in atherosclerotic lesions and also higher serum IL-1β and IL-18 in Ogg1(-/-)Ldlr(-/-) mice than in Ldlr(-/-). Transplantation with Ogg1(-/-) bone marrow into Ldlr(-/-) mice led to larger atherosclerotic lesions and increased IL-1β production. However, transplantation of Ogg1(-/-)Nlrp3(-/-) bone marrow reversed the Ogg1(-/-) phenotype of increased plaque size. Ogg1(-/-) macrophages showed increased oxidized mtDNA and had greater amounts of cytosolic mtDNA and cytochrome c, increased apoptosis, and more IL-1β secretion. Finally, we found that proatherogenic miR-33 can directly inhibit human OGG1 expression and indirectly suppress both mouse and human OGG1 via AMP-activated protein kinase.
  
  
  CONCLUSIONS
  OGG1 plays a protective role in atherogenesis by preventing excessive inflammasome activation. Our study provides insight into a new target for therapeutic intervention based on a link between oxidative mtDNA damage, OGG1, and atherosclerosis via NLRP3 inflammasome.
authors.affiliation: From the Departments of Pediatrics, Biomedical Sciences, and Infectious and Immunologic Diseases Research Center (IIDRC) (G.T., K.S., J.D., T.R.C., W.Z., S.C.), Department of Pathology (D.L.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Medicine, Barbra Streisand Women's Heart Center, Heart Institute of Cedars-Sinai (R.A.G.), Cedars-Sinai Medical Center, Los Angeles, CA; and David Geffen School of Medicine, University of California, Los Angeles (M.A.).
authors.forename: Gantsetseg
authors.initials: G
authors.lastname: Tumurkhuu
authors.affiliation: From the Departments of Pediatrics, Biomedical Sciences, and Infectious and Immunologic Diseases Research Center (IIDRC) (G.T., K.S., J.D., T.R.C., W.Z., S.C.), Department of Pathology (D.L.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Medicine, Barbra Streisand Women's Heart Center, Heart Institute of Cedars-Sinai (R.A.G.), Cedars-Sinai Medical Center, Los Angeles, CA; and David Geffen School of Medicine, University of California, Los Angeles (M.A.).
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shimada
authors.affiliation: From the Departments of Pediatrics, Biomedical Sciences, and Infectious and Immunologic Diseases Research Center (IIDRC) (G.T., K.S., J.D., T.R.C., W.Z., S.C.), Department of Pathology (D.L.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Medicine, Barbra Streisand Women's Heart Center, Heart Institute of Cedars-Sinai (R.A.G.), Cedars-Sinai Medical Center, Los Angeles, CA; and David Geffen School of Medicine, University of California, Los Angeles (M.A.).
authors.forename: Jargalsaikhan
authors.initials: J
authors.lastname: Dagvadorj
authors.affiliation: From the Departments of Pediatrics, Biomedical Sciences, and Infectious and Immunologic Diseases Research Center (IIDRC) (G.T., K.S., J.D., T.R.C., W.Z., S.C.), Department of Pathology (D.L.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Medicine, Barbra Streisand Women's Heart Center, Heart Institute of Cedars-Sinai (R.A.G.), Cedars-Sinai Medical Center, Los Angeles, CA; and David Geffen School of Medicine, University of California, Los Angeles (M.A.).
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Crother
authors.affiliation: From the Departments of Pediatrics, Biomedical Sciences, and Infectious and Immunologic Diseases Research Center (IIDRC) (G.T., K.S., J.D., T.R.C., W.Z., S.C.), Department of Pathology (D.L.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Medicine, Barbra Streisand Women's Heart Center, Heart Institute of Cedars-Sinai (R.A.G.), Cedars-Sinai Medical Center, Los Angeles, CA; and David Geffen School of Medicine, University of California, Los Angeles (M.A.).
authors.forename: Wenxuan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: From the Departments of Pediatrics, Biomedical Sciences, and Infectious and Immunologic Diseases Research Center (IIDRC) (G.T., K.S., J.D., T.R.C., W.Z., S.C.), Department of Pathology (D.L.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Medicine, Barbra Streisand Women's Heart Center, Heart Institute of Cedars-Sinai (R.A.G.), Cedars-Sinai Medical Center, Los Angeles, CA; and David Geffen School of Medicine, University of California, Los Angeles (M.A.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Luthringer
authors.affiliation: From the Departments of Pediatrics, Biomedical Sciences, and Infectious and Immunologic Diseases Research Center (IIDRC) (G.T., K.S., J.D., T.R.C., W.Z., S.C.), Department of Pathology (D.L.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Medicine, Barbra Streisand Women's Heart Center, Heart Institute of Cedars-Sinai (R.A.G.), Cedars-Sinai Medical Center, Los Angeles, CA; and David Geffen School of Medicine, University of California, Los Angeles (M.A.).
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Gottlieb
authors.affiliation: From the Departments of Pediatrics, Biomedical Sciences, and Infectious and Immunologic Diseases Research Center (IIDRC) (G.T., K.S., J.D., T.R.C., W.Z., S.C.), Department of Pathology (D.L.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Medicine, Barbra Streisand Women's Heart Center, Heart Institute of Cedars-Sinai (R.A.G.), Cedars-Sinai Medical Center, Los Angeles, CA; and David Geffen School of Medicine, University of California, Los Angeles (M.A.).
authors.forename: Shuang
authors.initials: S
authors.lastname: Chen
authors.affiliation: From the Departments of Pediatrics, Biomedical Sciences, and Infectious and Immunologic Diseases Research Center (IIDRC) (G.T., K.S., J.D., T.R.C., W.Z., S.C.), Department of Pathology (D.L.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Medicine, Barbra Streisand Women's Heart Center, Heart Institute of Cedars-Sinai (R.A.G.), Cedars-Sinai Medical Center, Los Angeles, CA; and David Geffen School of Medicine, University of California, Los Angeles (M.A.). moshe.arditi@cshs.org.
authors.forename: Moshe
authors.initials: M
authors.lastname: Arditi
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D045647:DNA Glycosylases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000502:physiology*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D066273:Diet, Western / Q000009:adverse effects; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse
keywords: DNA repair; atherosclerosis; inflammasomes; macrophages; mitochondria