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Single cell RNA sequencing of aortic CD45+ cells reveals aortic macrophage heterogeneity in mouse atherosclerosis

ABSTRACT: We have applied single cell RNA sequencing (scRNA-seq) as an unbiased transcriptomics to characterize aortic immune cells in atherosclerosis. The scRNA-seq analysis revealed macrophage heterogeneity at the single-cell level in mouse atherosclerotic aorta.

ORGANISM(S): Mus musculus

PROVIDER: GSE154692 | GEO | 2020/09/04

REPOSITORIES: GEO

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Project description:Background Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids and leukocytes within the arterial wall. By investigating the aortic transcriptome of atherosclerosis prone apolipoprotein E (ApoE-/-) mice, we aimed to identify new players in the development and progression of atherosclerosis. Methods RNA-Seq from aorta ApoE-/- mice was compared to healthy aorta. AnxA8 expression was assessed in human and mice atherosclerotic tissue and healthy aorta. ApoE-/- mice lacking systemic AnxA8 (ApoE-/-AnxA8-/-) were generated to assess the functional role of AnxA8. Bone marrow transplantation (BMT) was also done to generate ApoE-/- lacking AnxA8 specifically in bone marrow-derived cells. Intravital microscopy was used to analyze platelets and leukocyte adhesion in atheroprone mice. The role of AnxA8 was analyzed in cultured endothelial cells. Results RNA-Seq unveiled AnxA8 as one of the most significantly up-regulated genes in atherosclerotic aorta of ApoE-/- mice compared with wild type. Moreover, AnxA8 was also upregulated in human atherosclerotic plaques. Germline deletion of AnxA8 decreased atherosclerotic burden and atherosclerotic plaques size and volume in the aortic root. Plaques of ApoE-/-AnxA8-/- were characterized by a less lipid and inflammatory content compared with those in ApoE-/-AnxA8+/+. BMT showed that hematopoietic AnxA8 deficiency had no effect on atherosclerotic development. Oxidized-LDL (ox-LDL) increased AnxA8 mRNA and protein expression in murine aortic endothelial cells (MAECs). Subsequent in vitro experiments revealed that AnxA8 deficiency in MAECs suppressed P/E-selectin and CD31 expression and secretion induced by ox-LDL with a concomitant reduction in platelets and leukocyte adhesion. Intravital microscopy confirmed the decrease in leukocyte rolling and adhesion, and platelets adhesion, in ApoE-/-AnxA8-/- mice. Conclusion Our findings demonstrate that AnxA8 deficiency decreases atherosclerosis progression through regulating leukocyte infiltration and vascular inflammation.

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Single cell RNA sequencing of aortic CD45+ cells reveals aortic macrophage heterogeneity in mouse atherosclerosis

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