The tyrosin kinase Syk: A potential therapeutic target in atherosclerosis
Final Report Abstract
Like many other diseases, atherosclerosis stems from chronic inflammation of the vessel wall. This is initiated and entertained by various traditional and non-traditional risk factors, varying in response according to genetic background. Our group early on identified SYK as a potential therapeutic target. Here, we demonstrate that SYK indeed limits de novo atherogenesis and favorably alters early plaque phenotype. However, SYK failed to modulate preestablished, more advanced lesions in our hands. Also, SYK was not associated with disease or risk in the LURIC collective interrogated by high dimensional scRNAseq. However, with this project, we identify several cellular biomarkers and associated pathways that correlate both with coronary heart disease and long-term mortality. Our findings may have a profound impact on future risk stratification. Also, we demonstrate significant differences in the immune portfolio of murine and human atherosclerosis, potentially explaining why so many therapeutic endeavors succeed in mice but subsequently fail in humans.
Publications
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Atheroprotection through SYK inhibition fails in established disease when local macrophage proliferation dominates lesion progression. Basic Research in Cardiology, 111(2).
Lindau, Alexandra; Härdtner, Carmen; Hergeth, Sonja P.; Blanz, Kelly Daryll; Dufner, Bianca; Hoppe, Natalie; Anto-Michel, Nathaly; Kornemann, Jan; Zou, Jiadai; Gerhardt, Louisa M. S.; Heidt, Timo; Willecke, Florian; Geis, Serjosha; Stachon, Peter; Wolf, Dennis; Libby, Peter; Swirski, Filip K.; Robbins, Clinton S.; McPheat, William ... & Hilgendorf, Ingo
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Anti-inflammatory Strategies in Atherosclerosis. Hämostaseologie, 41(06), 433-442.
Bugger, Heiko & Zirlik, Andreas
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Identifying leukocyte phenotypes by scRNA-seq to predict cardiovascular risk. Nature Reviews Cardiology, 20(7), 439-440.
Gollmer, Johannes & Zirlik, Andreas
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Cross-species single-cell RNA sequencing reveals divergent phenotypes and activation states of adaptive immunity in human carotid and experimental murine atherosclerosis. Cardiovascular Research, 120(14), 1713–1726.
Horstmann, Hauke; Michel, Nathaly Anto; Sheng, Xia; Hansen, Sophie; Lindau, Alexandra; Pfeil, Katharina; Fernández, Marbely C; Marchini, Timoteo; Winkels, Holger; Mitre, Lucia Sol; Abogunloko, Tijani; Li, Xiaowei; Mwinyella, Timothy Bon-Nawul; Gissler, Mark Colin; Bugger, Heiko; Heidt, Timo; Buscher, Konrad; Hilgendorf, Ingo; Stachon, Peter ... & Wolf, Dennis
