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

Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the Interleukin (IL)-6 cytokine family, such as IL-6, oncostatin M, and cardiotrophin-1, have been extensively studied in atherosclerosis. However, the role of leukemia inhi...

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Vydáno v:European journal of pharmacology Ročník 985; s. 177121
Hlavní autoři: Hemme, Esmeralda, Depuydt, Marie A.C., van Santbrink, Peter J., Wezel, Anouk, Smeets, Harm J., Foks, Amanda C., Kuiper, Johan, Bot, Ilze
Médium: Journal Article
Jazyk:angličtina
Vydáno: Netherlands Elsevier B.V 15.12.2024
Témata:
Adhesion molecules
Animals
Atherosclerosis
Atherosclerosis - drug therapy
Atherosclerosis - metabolism
Atherosclerosis - pathology
Cholesterol
Cytokines
Endothelial Cells - drug effects
Endothelial Cells - metabolism
Female
Humans
Inflammation
Leukemia inhibitory factor
Leukemia Inhibitory Factor - genetics
Leukemia Inhibitory Factor - metabolism
Leukemia Inhibitory Factor Receptor alpha Subunit - genetics
Leukemia Inhibitory Factor Receptor alpha Subunit - metabolism
Mast Cells - drug effects
Mast Cells - metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Plaque, Atherosclerotic - drug therapy
Receptors, LDL - deficiency
Receptors, LDL - genetics
Adhesion molecules
Inflammation
Cytokines
Leukemia inhibitory factor
Cholesterol
Atherosclerosis
ISSN:0014-2999, 1879-0712, 1879-0712
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Shrnutí:Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the Interleukin (IL)-6 cytokine family, such as IL-6, oncostatin M, and cardiotrophin-1, have been extensively studied in atherosclerosis. However, the role of leukemia inhibitory factor (LIF), member of the IL-6 family, and its receptor (LIFR), remains to be further elucidated. Therefore, the aim of this study is to provide insight in LIF receptor signalling in atherosclerosis development. Single-cell RNA sequencing analysis of human carotid artery plaques revealed that mast cells highly express LIF, whereas LIFR was specifically expressed on activated endothelial cells. A similar expression pattern of Lifr was observed in mouse atherosclerotic plaques. Next, female Western-type diet fed Ldlr−/− mice were treated with LIF receptor inhibitor EC359 (5 mg/kg s.c., n = 15) or control solvent (n = 15) three times per week for eight weeks. Stenosis grade was reduced in the aortic root of EC359 treated mice compared to control mice, but treatment did not affect plaque composition. Serum cholesterol levels were significantly reduced in EC359 treated mice, likely attributed to a reduction in VLDL cholesterol levels. Furthermore, LIF receptor inhibition reduced Pecam1 and Vcam1 expression in the aorta. Consequently, immune cell infiltration was reduced in aortic plaques of EC359 treated mice compared to control mice. Conclusively, we demonstrated that LIF receptor is a potential therapeutic target in atherosclerosis by reducing plaque size, attributed to lower serum cholesterol levels, reduced endothelial activation and less immune cell infiltration in the plaque. •LIFR/Lifr is expressed on activated endothelial cells in human and mouse plaques.•In human carotid plaques, LIF is almost exclusively expressed by mast cells.•EC359 treatment limits plaque development in Ldlr−/− mice.•LIF receptor inhibition reduces endothelial cell activation in vivo and in vitro.•EC359 treatment lowers total cholesterol levels in serum of Ldlr−/− mice.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0014-2999
1879-0712
1879-0712
DOI:10.1016/j.ejphar.2024.177121