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

Liming Yu, Lin Xu, Haiyan Chu, Jun Peng, Anastasia Sacharidou, Hsi-hsien Hsieh, Ada Weinstock, Sohaib Khan, Liqian Ma, José Gabriel Barcia Durán, Jeffrey McDonald, Erik R. Nelson, Sunghee Park, Donald P. McDonnell, Kathryn J. Moore, Lily Jun-shen Huang, Edward A. Fisher, Chieko Mineo, Linzhang Huang () and Philip W. Shaul ()
Additional contact information
Liming Yu: University of Texas Southwestern Medical Center
Lin Xu: University of Texas Southwestern Medical Center
Haiyan Chu: University of Texas Southwestern Medical Center
Jun Peng: University of Texas Southwestern Medical Center
Anastasia Sacharidou: University of Texas Southwestern Medical Center
Hsi-hsien Hsieh: University of Texas Southwestern Medical Center
Ada Weinstock: New York University School of Medicine
Sohaib Khan: University of Cincinnati Cancer Center
Liqian Ma: University of Illinois at Urbana-Champaign
José Gabriel Barcia Durán: New York University School of Medicine
Jeffrey McDonald: University of Texas Southwestern Medical Center
Erik R. Nelson: University of Illinois at Urbana-Champaign
Sunghee Park: Duke University School of Medicine
Donald P. McDonnell: Duke University School of Medicine
Kathryn J. Moore: New York University School of Medicine
Lily Jun-shen Huang: University of Texas Southwestern Medical Center
Edward A. Fisher: New York University School of Medicine
Chieko Mineo: University of Texas Southwestern Medical Center
Linzhang Huang: Fudan University
Philip W. Shaul: University of Texas Southwestern Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39586-z

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