Kichi, Zahra Abedi

Mann Fallenbuchel, Elizabeth Josefina

Mazza, Tommaso

Natarelli, Lucia

Parca, Luca

Weber, Christian

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

Open Data LMU (Ludwig-Maximilians-Universität München)

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

https://data.ub.uni-muenchen.de/352/2/Natarelli_et_al_Main_manuscript.pdf

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

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Open Data LMU (Ludwig-Maximilians-Universität München)