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Macrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice.

Authors :
Yu, Liming
Xu, Lin
Chu, Haiyan
Peng, Jun
Sacharidou, Anastasia
Hsieh, Hsi-hsien
Weinstock, Ada
Khan, Sohaib
Ma, Liqian
Durán, José Gabriel Barcia
McDonald, Jeffrey
Nelson, Erik R.
Park, Sunghee
McDonnell, Donald P.
Moore, Kathryn J.
Huang, Lily Jun-shen
Fisher, Edward A.
Mineo, Chieko
Huang, Linzhang
Shaul, Philip W.
Source :
Nature Communications; 7/25/2023, Vol. 14 Issue 1, p1-17, 17p
Publication Year :
2023

Abstract

Hypercholesterolemia and vascular inflammation are key interconnected contributors to the pathogenesis of atherosclerosis. How hypercholesterolemia initiates vascular inflammation is poorly understood. Here we show in male mice that hypercholesterolemia-driven endothelial activation, monocyte recruitment and atherosclerotic lesion formation are promoted by a crosstalk between macrophages and endothelial cells mediated by the cholesterol metabolite 27-hydroxycholesterol (27HC). The pro-atherogenic actions of macrophage-derived 27HC require endothelial estrogen receptor alpha (ERα) and disassociation of the cytoplasmic scaffolding protein septin 11 from ERα, leading to extranuclear ERα- and septin 11-dependent activation of NF-κB. Furthermore, pharmacologic inhibition of cyp27a1, which generates 27HC, affords atheroprotection by reducing endothelial activation and monocyte recruitment. These findings demonstrate cell-to-cell communication by 27HC, and identify a major causal linkage between the hypercholesterolemia and vascular inflammation that partner to promote atherosclerosis. Interventions interrupting this linkage may provide the means to blunt vascular inflammation without impairing host defense to combat the risk of atherosclerotic cardiovascular disease that remains despite lipid-lowering therapies. Hypercholesterolemia and vascular inflammation both contribute to the pathogenesis of atherosclerosis, but how hypercholesterolemia initiates vascular inflammation is not fully understood. Here the authors report that crosstalk between macrophages and endothelial cells mediated by the cholesterol metabolite 27-hydroxycholesterol drives vascular inflammation and contributes to atherosclerosis in male mice. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
20411723
Volume :
14
Issue :
1
Database :
Complementary Index
Journal :
Nature Communications
Publication Type :
Academic Journal
Accession number :
166736764
Full Text :
https://doi.org/10.1038/s41467-023-39586-z