Details

Autor(en) / Beteiligte

• Quiles-Jiménez, Ana
• Gregersen, Ida
• Segers, Filip M.
• Skarpengland, Tonje
• Kroustallaki, Penelope
• Yang, Kuan
• Kong, Xiang Yi
• Lauritzen, Knut H.
• Olsen, Maria B.
• Karlsen, Tom Rune
• Nyman, Tuula A.
• Sagen, Ellen L.
• Bjerkeli, Vigdis
• Suganthan, Rajikala
• Nygård, Ståle
• Scheffler, Katja
• Prins, Jurriën
• Van der Veer, Eric
• Øgaard, Jonas DS
• Fløisand, Yngvar
• Jørgensen, Helle F.
• Holven, Kirsten B.
• Biessen, Erik A.
• Nilsen, Hilde
• Dahl, Tuva B.
• Holm, Sverre
• Bennett, Martin R.
• Aukrust, Pål
• Bjørås, Magnar
• Halvorsen, Bente

Titel

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

Ist Teil von

• Atherosclerosis, 2021-05, Vol.324, p.123-132

Ort / Verlag

Ireland: Elsevier B.V

Erscheinungsjahr

2021

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• 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 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. 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. Our findings show that Neil3 deficiency promotes atherosclerosis development through non-canonical mechanisms affecting VSMC phenotype involving activation of the Akt signaling pathway. [Display omitted] •Apoe−/−/Neil3−/− mice develop more atherosclerosis as compared to Apoe−/− mice.•Apoe−/−/Neil3−/− mice display increased medial VSMC area and layer disorganization.•Increased aortic VSMC proliferation in Apoe−/−/Neil3−/− mice and NEIL3-deficient primary human VSMCs.•Neil3 deficiency increases aortic VSMC phenotypic transdifferentiation towards an atherosclerotic macrophage-like cells.•Neil3/NEIL3 deficiency-dependent VSMC proliferation involves activation of the Akt signaling pathway.