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Citation: Natarelli, Lucia and Kichi, Zahra Abedi and Mann Fallenbuchel, Elizabeth Josefina and Parca, Luca and Mazza, Tommaso and Weber, Christian: Supplementary data from: Role of endothelial micronuclei-contained DNA in atherosclerosis. 22. December 2022. Open Data LMU. 10.5282/ubm/data.352

Supplementary data from: Role of endothelial micronuclei-contained DNA in atherosclerosis
Supplementary data from: Role of endothelial micronuclei-contained DNA in atherosclerosis

Atherosclerosis is a complex disease that is often associated with hyperlipidaemia and affects the vessel tree under altered haemodynamic forces. However, shear stress is not itself responsible for the pathogenesis of atherosclerosis. Chromosomal mutations and DNA damage have emerged as key epigenetic signatures responsible for regional phenotypic heterogeneity, particularly in the endothelial cells (ECs) lining the arterial tree. We have previously reported that aortic ECs have a physiological tendency to accumulate damage in micronuclei (MN), which are usually generated in hyperproliferative cells. Hyperlipidaemia exacerbates DNA damage and MN formation in these ECs, but the interplay between endothelial MN and atherosclerosis is unknown. Here, we showed that low shear stress physiologically promoted MN formation in proliferative human ECs, whereas hyperlipidaemia enhanced the formation of pathological MN with DNA damage (pathological). DNA signatures were investigated by WGS of MN and the main nuclei containing DNA in synthesis or damaged. Duplications of known atherosclerosis susceptibility loci were found in physiological MN. Pathological MN contain duplications of pro-inflammatory genes, and mutations in cell cycle checkpoint and DNA damage repair genes. The transcriptional relevance of all key DNA damage repair markers of homologous recombination was confirmed. Hyperlipidaemia enhanced the accumulation of MN with defects in lamin B1, which is involved in double strand break repair through relocating damaged DNA at the nuclear periphery. Together, our findings indicated a role of DNA signatures that are relocated to endothelial MN in atherosclerosis and accumulate under impaired DNA repair.

atherosclerosis, DNA damage, endothelial cells, micronuclei
Natarelli, Lucia
Kichi, Zahra Abedi
Mann Fallenbuchel, Elizabeth Josefina
Parca, Luca
Mazza, Tommaso
Weber, Christian
2022

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DOI: 10.5282/ubm/data.352

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Abstract

Atherosclerosis is a complex disease that is often associated with hyperlipidaemia and affects the vessel tree under altered haemodynamic forces. However, shear stress is not itself responsible for the pathogenesis of atherosclerosis. Chromosomal mutations and DNA damage have emerged as key epigenetic signatures responsible for regional phenotypic heterogeneity, particularly in the endothelial cells (ECs) lining the arterial tree. We have previously reported that aortic ECs have a physiological tendency to accumulate damage in micronuclei (MN), which are usually generated in hyperproliferative cells. Hyperlipidaemia exacerbates DNA damage and MN formation in these ECs, but the interplay between endothelial MN and atherosclerosis is unknown. Here, we showed that low shear stress physiologically promoted MN formation in proliferative human ECs, whereas hyperlipidaemia enhanced the formation of pathological MN with DNA damage (pathological). DNA signatures were investigated by WGS of MN and the main nuclei containing DNA in synthesis or damaged. Duplications of known atherosclerosis susceptibility loci were found in physiological MN. Pathological MN contain duplications of pro-inflammatory genes, and mutations in cell cycle checkpoint and DNA damage repair genes. The transcriptional relevance of all key DNA damage repair markers of homologous recombination was confirmed. Hyperlipidaemia enhanced the accumulation of MN with defects in lamin B1, which is involved in double strand break repair through relocating damaged DNA at the nuclear periphery. Together, our findings indicated a role of DNA signatures that are relocated to endothelial MN in atherosclerosis and accumulate under impaired DNA repair.

Keywords

atherosclerosis, DNA damage, endothelial cells, micronuclei

References

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Item Type:Data
Contact Person:Natarelli, Lucia
E-Mail of Contact:lucia.natarelli at med.uni-muenchen.de
Subjects:Faculty of Medicine
Faculty of Biology
Dewey Decimal Classification:600 Natural sciences and mathematics
600 Natural sciences and mathematics > 570 Life sciences
600 Technology, Medicine
600 Technology, Medicine > 610 Medical sciences and medicine
ID Code:352
Deposited By: Dr. Lucia Natarelli
Deposited On:23. Dec 2022 10:24
Last Modified:16. Jan 2023 13:18

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