title: Enhanced base excision repair capacity in carotid atherosclerosis may protect nuclear DNA but not mitochondrial DNA.
abstract: Lesional and systemic oxidative stress has been implicated in the pathogenesis of atherosclerosis, potentially leading to accumulation of DNA base lesions within atherosclerotic plaques. Although base excision repair (BER) is a major pathway counteracting oxidative DNA damage, our knowledge on BER and accumulation of DNA base lesions in clinical atherosclerosis is scarce. Here, we evaluated the transcriptional profile of a wide spectrum of BER components as well as DNA damage accumulation in atherosclerotic and non-atherosclerotic arteries.
  
  
  
  BER gene expression levels were analyzed in 162 carotid plaques, 8 disease-free carotid specimens from patients with carotid plaques and 10 non-atherosclerotic control arteries. Genomic integrity, mitochondrial (mt) DNA copy number, oxidative DNA damage and BER proteins were evaluated in a subgroup of plaques and controls.
  
  
  
  Our major findings were: (i) The BER pathway showed a global increased transcriptional response in plaques as compared to control arteries, accompanied by increased expression of several BER proteins. (ii) Whereas nuclear DNA stability was maintained within carotid plaques, mtDNA integrity and copy number were decreased. (iii) Within carotid plaques, mRNA levels of several BER genes correlated with macrophage markers. (iv) In vitro, some of the BER genes were highly expressed in the anti-inflammatory and pro-resolving M2 macrophages, showing increased expression upon exposure to modified lipids.
  
  
  
  The increased transcriptional response of BER genes in atherosclerosis may contribute to lesional nuclear DNA stability but appears insufficient to maintain mtDNA integrity, potentially influencing mitochondrial function in cells within the atherosclerotic lesion.
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Electronic address: Tonje.Skarpengland@rr-research.no.
authors.forename: Tonje
authors.initials: T
authors.lastname: Skarpengland
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Tuva B
authors.initials: TB
authors.lastname: Dahl
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Department of Neurology, Oslo University Hospital Rikshospitalet, Norway.
authors.forename: Mona
authors.initials: M
authors.lastname: Skjelland
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Katja
authors.initials: K
authors.lastname: Scheffler
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; PROMEC Core Facility for Proteomics and Metabolomics, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Mirta Mittelsted Leal
authors.initials: MML
authors.lastname: de Sousa
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Ida
authors.initials: I
authors.lastname: Gregersen
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; PROMEC Core Facility for Proteomics and Metabolomics, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Anna
authors.initials: A
authors.lastname: Kuśnierczyk
authors.affiliation: PROMEC Core Facility for Proteomics and Metabolomics, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Animesh
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; PROMEC Core Facility for Proteomics and Metabolomics, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Slupphaug
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Eide
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway.
authors.forename: Filip M
authors.initials: FM
authors.lastname: Segers
authors.affiliation: Department of Neurology, Oslo University Hospital Rikshospitalet, Norway.
authors.forename: Karolina Ryeng
authors.initials: KR
authors.lastname: Skagen
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Department of Cardiology, Oslo University Hospital Rikshospitalet, Norway; Center of Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Christen P
authors.initials: CP
authors.lastname: Dahl
authors.affiliation: Department of Neurology, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: David
authors.initials: D
authors.lastname: Russell
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Copenhagen, Denmark.
authors.forename: Lasse
authors.initials: L
authors.lastname: Folkersen
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Krohg-Sørensen
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Lillehammer Hospital for Rheumatic Diseases, Lillehammer, Norway.
authors.forename: Sverre
authors.initials: S
authors.lastname: Holm
authors.affiliation: Department of Microbiology, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Magnar
authors.initials: M
authors.lastname: Bjørås
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway.
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
mesh_terms: D000368:Aged; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology; D002340:Carotid Artery Diseases / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial
keywords: Atherosclerosis; Base excision repair; DNA damage; DNA glycosylases