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Nature. 2019 May;569(7757):565-569. doi: 10.1038/s41586-019-1140-4. Epub 2019 Apr 24.

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

Author information

1
Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
2
Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
3
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
4
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.
5
Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
6
Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
7
Department of Medicine, New York University School of Medicine, New York, NY, USA.
8
Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY, USA.
9
Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, NY, USA.
10
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
11
Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
12
Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
13
Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA. philip.shaul@utsouthwestern.edu.

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.

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PMID:
31019307
PMCID:
PMC6631346
DOI:
10.1038/s41586-019-1140-4
[Indexed for MEDLINE]
Free PMC Article

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