The DNA glycosylase Neil3 - a metabolic sensor in atherogenesis

In the current project we hypothesized that DNA glycosylases play an important role in atherogenesis. This hypothesis has been be tested in experimental and clinical studies with focus on (a) studies in mice that are deficient in Neil3 glycosylase and that are prone to develop atherosclerosis; (b) studies on the regulation of the DNA glycosylase Neil3 in human atherosclerotic lesions. The project has studied novel molecular mechanisms in the development of atherosclerosis, dealing with previously unaddressed issues in the intersection between cardiovascular medicine and molecular biology. DNA repair mechanisms have previously not been linked to atherosclerosis and we have shown that Neil3 enzyme in the base excision repair pathway can represent a novel target for therapy in this disorder. Among the data generated, we show that TET2, the master key of epigenetic changes, is highly regulated in carotid explants upon atherosclerotic development in association with Neil3. In addition, we have discovered that Neil3 controls the intestinal function pointing to an important role of Neil3 in metabolism. Atherosclerosis is a leading cause of death and loss of productive life years in Norway and worldwide. The development of new therapeutic options and novel biomarkers may therefore have important consequences for the society.

Prosjektet er av natur nyskapende og har generert ny kunnskap rundt prosesser involvert i sykdomsprosesser knyttet opp mot hjerte-kar sykdommer. Virkningen av ny kunnskap er at den ofte reiser ny spørsmål som vil kreve nye studier (effekten). Effekten konkret for prosjektet er at vi har identifisert enkeltfaktorer som driver av sykdomsprosesser. Foreløpig kan vi ikke si helt sikkert hva helseeffekten av kunnskapen generte i prosjektet. Men potensialet av funn er av en slik at det vil danne grunnlag for nye studier. Prosjektet har hatt betydning for utdannelse av en postdoktor og en PhD kandidat, samt bedret synergier med både nasjonale og internasjonale samarbeidspartnere.

Atherosclerosis is major cause of myocardial infarction and ischemic stroke, and is a substantial economic and social burden to the health care system both in Norway and worldwide. The development of novel biomarkers and new therapeutic options will have important consequences for both the patients and the society. Studies on pathogenic mechanisms in atherosclerosis are required for the development of new treatment option in these disorders. Our hypothesis is that the DNA glycosylase, Neil3, can play an important role by modulating the development and progression of atherosclerosis, and we propose Neil3 as a senor of metabolic stress which causes epigenetic modulation that can induce the transcription of factors that can counteracts atherosclerotic disease progression. This hypothesis will be tested through various approaches including (i) studies in mice that deficient in Neil3 and prone to develop atherosclerosis fed on high fat and chow diet to vary the metabolic stress; (ii) studies of Neil3 and epigenetic modifications in human atherosclerotic lesions and in leukocytes from patients with cardiovascular disease or at risk for developing such disorders. (iii) We will further test if Neil3 interacts with the metabolic sensor LXRa in the transitions of metabolic stress to epigenetic modifications of DNA during atherogenesis. This project attempts to study novel molecular mechanisms in the development of atherosclerosis, and deals with previously unaddressed issues in the intersection between cardiovascular medicine and molecular biology. DNA repair mechanisms have previously not been linked to the pathogenesis of atherosclerosis, and our preliminary data suggest a role for Neil3 beyond that of DNA repair involving lipid metabolism which imply modulation of the epigenetic signature and its translation to altered gene transcription. These pathways could represent a novel target for therapy in atherosclerotic disorders.