1. Targeting the phenotypic switch of vascular smooth muscle cells to tackle atherosclerosis
- Author
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Gaetano Santulli, Stanislovas S. Jankauskas, Jessica Gambardella, Urna Kansakar, Kansakar, U., Jankauskas, S. S., Gambardella, J., and Santulli, G.
- Subjects
Vascular smooth muscle ,Mice, Knockout, ApoE ,Myocytes, Smooth Muscle ,TDG ,OCT4 ,Article ,Muscle, Smooth, Vascular ,MYOCD ,DNA Glycosylases ,Mice ,Phenotype switch ,Animals ,Humans ,N-Glycosyl Hydrolases ,Cells, Cultured ,Cell Proliferation ,Endodeoxyribonucleases ,Chemistry ,VSMC ,p27 ,Atherosclerosis ,Phenotype ,Plaque, Atherosclerotic ,Cell biology ,Mice, Inbred C57BL ,Atherosclerosi ,KFL4 ,Cardiology and Cardiovascular Medicine ,Human - Abstract
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.Chow diet-fed atherosclerosis-prone ApoeWe 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.Our findings show that Neil3 deficiency promotes atherosclerosis development through non-canonical mechanisms affecting VSMC phenotype involving activation of the Akt signaling pathway.
- Published
- 2021
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