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DNA glycosylase Neil3 regulates vascular smooth muscle cell biology during atherosclerosis development.

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Quiles-Jiménez, Ana 
Gregersen, Ida 
Segers, Filip M 
Skarpengland, Tonje 
Kroustallaki, Penelope 


BACKGROUND AND AIMS: Atherogenesis involves a complex interaction between immune cells and lipids, processes greatly influenced by the vascular smooth muscle cell (VSMC) phenotype. The DNA glycosylase NEIL3 has previously been shown to have a role in atherogenesis, though whether this is due to its ability to repair DNA damage or to other non-canonical functions is not yet clear. Hereby, we investigate the role of NEIL3 in atherogenesis, specifically in VSMC phenotypic modulation, which is critical in plaque formation and stability. METHODS: Chow diet-fed atherosclerosis-prone Apoe-/- mice deficient in Neil3, and NEIL3-abrogated human primary aortic VSMCs were characterized by qPCR, and immunohistochemical and enzymatic-based assays; moreover, single-cell RNA sequencing, mRNA sequencing, and proteomics were used to map the molecular effects of Neil3/NEIL3 deficiency in the aortic VSMC phenotype. Furthermore, BrdU-based proliferation assays and Western blot were performed to elucidate the involvement of the Akt signaling pathway in the transdifferentiation of aortic VSMCs lacking Neil3/NEIL3. RESULTS: We show that Neil3 deficiency increases atherosclerotic plaque development without affecting systemic lipids. This observation was associated with a shift in VSMC phenotype towards a proliferating, lipid-accumulating and secretory macrophage-like cell phenotype, without changes in DNA damage. VSMC transdifferentiation in Neil3-deficient mice encompassed increased activity of the Akt signaling pathway, supported by cell experiments showing Akt-dependent proliferation in NEIL3-abrogated human primary aortic VSMCs. CONCLUSIONS: Our findings show that Neil3 deficiency promotes atherosclerosis development through non-canonical mechanisms affecting VSMC phenotype involving activation of the Akt signaling pathway.



Akt signaling, Atherosclerosis, DNA damage repair, NEIL3, Phenotypic transdifferentiation, Vascular smooth muscle cells, Animals, Atherosclerosis, Cell Proliferation, Cells, Cultured, DNA Glycosylases, Endodeoxyribonucleases, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, ApoE, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, N-Glycosyl Hydrolases, Phenotype, Plaque, Atherosclerotic

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Elsevier BV
British Heart Foundation (CH/2000003)
British Heart Foundation (CH/2000003/12800)
British Heart Foundation (PG/19/6/34153)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (PG/16/11/32021)
British Heart Foundation (RG/20/2/34763)