|Clin Res Cardiol (2021). 10.1007/s00392-021-01933-9
|The spatio-temporal development of macrophages in the course of atherosclerosis|
|T.-S. Dederichs1, C. Härdtner1, B. Dufner1, C. Bode1, I. Hilgendorf1|
|1Klinik für Kardiologie und Angiologie I, Universitäts-Herzzentrum Freiburg - Bad Krozingen GmbH, Freiburg im Breisgau;|
Hypercholesterolemia-driven atherosclerosis is a systemic and chronic inflammatory disease propagated by macrophage accumulation in the plaque. In depth profiling of atheromatous plaque macrophages over the course of disease will provide a better understanding of mechanisms which drive plaque progression and aid in identifying unique therapeutic targets.
We aimed at characterizing changes in site-specific murine monocyte/macrophages, i.e. atherosclerotic aorta, remote peritoneum, and blood circulation, in the course of atherosclerosis.
Results and Methods
Apolipoprotein E knock-out (APOE-/-) mice receiving 0, 1 and 6 month of HFD developed hypercholesterolemia and atheroma with plaque lipid deposition covering 8% (1 month) and 32% (6 months) of the aortic inner lining, respectively. At each time point, aortic macrophages, peritoneal macrophages as well as circulating/splenic monocytes were sorted from the same organisms for bulk-RNA-sequencing. Whole transcriptome profiling showed a continuous upregulation of genes in aortic macrophages, whereas the number of expressed genes of remote monocytes/macrophages went down. In addition, we identified nearly 400 DEGs uniquely regulated in the aortic macrophages and specified the regulation pattern at different stages of the disease. More than 60% DEGs of aortic macrophages ascended in the time of atheroma initiation and kept at a relatively uplifted level. Gene ontology analysis revealed a handful of biological processes specifically enriched in aortic macrophages, such as regulation of macrophage-derived foam cell differentiation, positive regulation of lipid transport, negative regulation of leukocyte migration, and response to tumor necrosis factors.
We identified distinct biological processes linked to atheroma formation and progression as well as uniquely regulated genes in atheromatous aortic macrophages that may serve as novel therapeutic targets. Additionally, our dataset characterized the regulation pattern of all the DEGs, which may potentially support the execution of therapeutic intervention at the right disease stages.