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Leukemia inhibitory factor receptor inhibition by EC359 reduces atherosclerotic stenosis grade in Ldlr-/- mice

  • 0Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
European Journal of Pharmacology +

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November 11, 2024

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November 11, 2024

View abstract on PubMed

Summary

This summary is machine-generated.

Leukemia inhibitory factor receptor (LIFR) inhibition reduced atherosclerosis plaque size in mice. This was achieved by lowering cholesterol, reducing endothelial activation, and decreasing immune cell infiltration, suggesting LIFR as a therapeutic target.

Area Of Science

  • Cardiovascular Biology
  • Immunology
  • Molecular Medicine

Background

  • Cytokines, particularly the Interleukin-6 (IL-6) family, are implicated in atherosclerosis progression.
  • The specific role of leukemia inhibitory factor (LIF) and its receptor (LIFR) in atherosclerosis requires further investigation.

Purpose Of The Study

  • To investigate the role of LIF receptor signaling in the development of atherosclerosis.
  • To determine if LIFR inhibition can serve as a therapeutic strategy for atherosclerosis.

Main Methods

  • Single-cell RNA sequencing of human carotid artery plaques to identify LIF and LIFR expression.
  • Treatment of Western-type diet-fed Ldlr-/- mice with a LIF receptor inhibitor (EC359) or control solvent.
  • Analysis of aortic root stenosis, plaque composition, serum lipid profiles, aortic gene expression (Pecam1, Vcam1), and immune cell infiltration.

Main Results

  • LIFR was specifically expressed on activated endothelial cells in human and mouse atherosclerotic plaques, while LIF was highly expressed on mast cells.
  • LIFR inhibition with EC359 reduced stenosis grade in the aortic root of mice.
  • Treatment led to significantly reduced serum cholesterol levels, particularly VLDL, and decreased Pecam1 and Vcam1 expression in the aorta.
  • Immune cell infiltration into aortic plaques was reduced in EC359-treated mice.

Conclusions

  • LIF receptor signaling plays a significant role in atherosclerosis development.
  • Inhibition of LIFR represents a potential therapeutic target for atherosclerosis.
  • Therapeutic benefits include reduced plaque size, lower serum cholesterol, attenuated endothelial activation, and decreased immune cell infiltration.

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