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, Philip W. Shaul

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17 Scopus citations

Abstract

Atherosclerosis, which underlies life-threatening cardiovascular disorders such as myocardial infarction and stroke 1 , 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 development 2,3 . 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.

Original languageEnglish (US)
JournalNature
DOIs
StatePublished - Jan 1 2019

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ASJC Scopus subject areas

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Cite this

Huang, L., Chambliss, K. L., Gao, X., Yuhanna, I. S., Behling-Kelly, E., Bergaya, S., Ahmed, M., Michaely, P., Luby-Phelps, K., Darehshouri, A., Xu, L., Fisher, E. A., Ge, W. P., Mineo, C., & Shaul, P. W. (2019). SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis. Nature. https://doi.org/10.1038/s41586-019-1140-4