Abstract
Increasing evidence suggests that oxidative DNA damage accumulates in atherosclerosis. Recently, we showed that a genetic variant in the human DNA repair enzyme NEIL3 was associated with increased risk of myocardial infarction. Here, we explored the role of Neil3/NEIL3 in atherogenesis by both clinical and experimental approaches. Human carotid plaques revealed increased NEIL3 mRNA expression which significantly correlated with mRNA levels of the macrophage marker CD68. Apoe−/−Neil3−/− mice on high-fat diet showed accelerated plaque formation as compared to Apoe−/− mice, reflecting an atherogenic lipid profile, increased hepatic triglyceride levels and attenuated macrophage cholesterol efflux capacity. Apoe−/−Neil3−/− mice showed marked alterations in several pathways affecting hepatic lipid metabolism, but no genotypic alterations in genome integrity or genome-wide accumulation of oxidative DNA damage. These results suggest a novel role for the DNA glycosylase Neil3 in atherogenesis in balancing lipid metabolism and macrophage function, potentially independently of genome-wide canonical base excision repair of oxidative DNA damage.
Highlights
Increasing evidence suggests that oxidative DNA damage accumulates in atherosclerosis
We first examined if NEIL3 gene expression was regulated in clinical atherosclerosis by assessing transcript levels in human carotid plaques of two different study populations (i.e., Biobank of Karolinska Endarterectomies [BiKE] of Stockholm [Supplementary Table S1]10 and Biobank of Oslo [Supplementary Table S2])
In BiKE, microarray analyses revealed increased NEIL3 expression in plaques (n = 106) as compared to non-atherosclerotic control arteries (n = 10, iliac arteries from organ donors, 3 females/7 males, median age 54 years, range 30–61 years) (Fig. 1A). These findings were replicated by RT-qPCR analysis of carotid plaques (n = 68) and non-atherosclerotic control arteries (n = 9, iliac arteries from organ donors, 2 females/7 males, median age 37 years, range 15–62 years) of the Biobank of Oslo, with enhanced NEIL3 mRNA levels in carotid plaques (Fig. 1B)
Summary
Increasing evidence suggests that oxidative DNA damage accumulates in atherosclerosis. Apoe−/−Neil3−/− mice showed marked alterations in several pathways affecting hepatic lipid metabolism, but no genotypic alterations in genome integrity or genome-wide accumulation of oxidative DNA damage. These results suggest a novel role for the DNA glycosylase Neil[3] in atherogenesis in balancing lipid metabolism and macrophage function, potentially independently of genome-wide canonical base excision repair of oxidative DNA damage. Oxidative stress has been widely accepted as an important feature of atherosclerosis Oxidative stress induces both nuclear and mitochondrial DNA damage, and accumulation of DNA damage has been reported in atherosclerotic lesions[2]. BER is initiated by a lesion-specific DNA glycosylase that removes the damaged base to generate an abasic site (AP site). Neil[3] appears to play a role in regeneration after cerebral hypoxic ischemic injury[9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
