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Trial Lecture – time and place
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Adjudication committee
- First opponent: Professor Allan Sirsjö, Ørebro University
- Second opponent: Professor Tor Gjøen, Faculty of Mathematics and Natural Sciences, University of Oslo
- Third member and chair of the evaluation committee: Researcher Cathrine Rein Carlson, University of Oslo
Chair of the Defence
Professor emerita Ingebjørg Seljeflot, Faculty of Medicine, University of Oslo
Principal Supervisor
Professor Bente Evy Halvorsen, Faculty of Medicine, University of Oslo
Summary
Cardiovascular disease (CVD), which includes cerebral stroke and myocardial infarction, comprises a significant risk to public health, in addition to being a major financial burden in society. The most important cause behind CVD is atherosclerosis. Even though we are familiar with several risk factors underlying atherosclerosis, there is a lot we do not know about the initiation and progression of the disease.
Endonuclease VIII-like glycosylase 3 (NEIL3) is an enzyme that repairs oxidized (damaged) bases in DNA. Previous research suggests that certain polymorphisms of NEIL3 are associated with increased risk of myocardial infarction. The aim of this thesis is to explore this relationship further, using mouse models prone to atherosclerosis.
It was shown that NEIL3-deficient mice develop more atherosclerosis than control mice. The increased atherosclerosis was not associated with increased lipid levels or inflammatory markers in the blood, nor with increased DNA damage in the cells. However, smooth muscle cells in the arterial wall of NEIL3-deficient mice exhibited a pro-atherogenic and proliferative phenotype.
Furthermore, gut microbiota-dependent metabolites were found at differing levels in the plasma when comparing NEIL3-deficient mice and control mice. Investigations of the bowel showed that the gut microbiota had a different composition between the two groups, and there was increased gut permeability in NEIL3-deficient mice.
Telomeres, DNA-protecting structures which shorten with age, were shorter in NEIL3-deficient than in control mice. Also, hematopoietic cell numbers were decreased both in the bone marrow and in peripheral blood. This suggests that NEIL3 has an essential telomere-protecting function in vivo.
These findings confirm and elaborate on previous research done on NEIL3, and suggest mechanisms linking NEIL3-deficiency and increased atherosclerosis.
Additional information
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