SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis

Linzhang Huang, Ken L. Chambliss, Xiaofei Gao, Ivan S. Yuhanna, Erica Behling-Kelly, Sonia Bergaya, Mohamed Ahmed, Peter Michaely, Kate Luby-Phelps, Anza Darehshouri, Lin Xu, Edward A. Fisher, Woo-Ping Ge, Chieko Mineo and Philip W. Shaul ()
Additional contact information
Linzhang Huang: University of Texas Southwestern Medical Center
Ken L. Chambliss: University of Texas Southwestern Medical Center
Xiaofei Gao: University of Texas Southwestern Medical Center
Ivan S. Yuhanna: University of Texas Southwestern Medical Center
Erica Behling-Kelly: University of Texas Southwestern Medical Center
Sonia Bergaya: New York University School of Medicine
Mohamed Ahmed: University of Texas Southwestern Medical Center
Peter Michaely: University of Texas Southwestern Medical Center
Kate Luby-Phelps: University of Texas Southwestern Medical Center
Anza Darehshouri: University of Texas Southwestern Medical Center
Lin Xu: University of Texas Southwestern Medical Center
Edward A. Fisher: New York University School of Medicine
Woo-Ping Ge: University of Texas Southwestern Medical Center
Chieko Mineo: University of Texas Southwestern Medical Center
Philip W. Shaul: University of Texas Southwestern Medical Center

Nature, 2019, vol. 569, issue 7757, 565-569

Abstract: Abstract Atherosclerosis, which underlies life-threatening cardiovascular disorders such as myocardial infarction and stroke1, is initiated by passage of low-density lipoprotein (LDL) cholesterol into the artery wall and its engulfment by macrophages, which leads to foam cell formation and lesion development2,3. It is unclear how circulating LDL enters the artery wall to instigate atherosclerosis. Here we show in mice that scavenger receptor class B type 1 (SR-B1) in endothelial cells mediates the delivery of LDL into arteries and its accumulation by artery wall macrophages, thereby promoting atherosclerosis. LDL particles are colocalized with SR-B1 in endothelial cell intracellular vesicles in vivo, and transcytosis of LDL across endothelial monolayers requires its direct binding to SR-B1 and an eight-amino-acid cytoplasmic domain of the receptor that recruits the guanine nucleotide exchange factor dedicator of cytokinesis 4 (DOCK4)4. DOCK4 promotes internalization of SR-B1 and transport of LDL by coupling the binding of LDL to SR-B1 with activation of RAC1. The expression of SR-B1 and DOCK4 is increased in atherosclerosis-prone regions of the mouse aorta before lesion formation, and in human atherosclerotic arteries when compared with normal arteries. These findings challenge the long-held concept that atherogenesis involves passive movement of LDL across a compromised endothelial barrier. Interventions that inhibit the endothelial delivery of LDL into artery walls may represent a new therapeutic category in the battle against cardiovascular disease.

Date: 2019
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DOI: 10.1038/s41586-019-1140-4

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