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 A Michaely, Katherine J Phelps, Anza Darehshouri, Lin Xu, Edward A. Fisher, Wuping Ge, Chieko Mineo, Philip W Shaul

Research output: Contribution to journalLetter

5 Citations (Scopus)

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

Fingerprint

CD36 Antigens
Transcytosis
Cytokinesis
LDL Lipoproteins
Atherosclerosis
Endothelial Cells
Cell Count
Arteries
Macrophages
Guanine Nucleotide Exchange Factors
Foam Cells
Cytoplasmic and Nuclear Receptors
LDL Cholesterol
Aorta
Cardiovascular Diseases
Stroke
Myocardial Infarction
Amino Acids

ASJC Scopus subject areas

  • General

Cite this

SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis. / Huang, Linzhang; Chambliss, Ken L.; Gao, Xiaofei; Yuhanna, Ivan S.; Behling-Kelly, Erica; Bergaya, Sonia; Ahmed, Mohamed; Michaely, Peter A; Phelps, Katherine J; Darehshouri, Anza; Xu, Lin; Fisher, Edward A.; Ge, Wuping; Mineo, Chieko; Shaul, Philip W.

In: Nature, 01.01.2019.

Research output: Contribution to journalLetter

Huang, L, Chambliss, KL, Gao, X, Yuhanna, IS, Behling-Kelly, E, Bergaya, S, Ahmed, M, Michaely, PA, Phelps, KJ, Darehshouri, A, Xu, L, Fisher, EA, Ge, W, Mineo, C & Shaul, PW 2019, 'SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis', Nature. https://doi.org/10.1038/s41586-019-1140-4
Huang L, Chambliss KL, Gao X, Yuhanna IS, Behling-Kelly E, Bergaya S et al. SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis. Nature. 2019 Jan 1. https://doi.org/10.1038/s41586-019-1140-4
Huang, Linzhang ; Chambliss, Ken L. ; Gao, Xiaofei ; Yuhanna, Ivan S. ; Behling-Kelly, Erica ; Bergaya, Sonia ; Ahmed, Mohamed ; Michaely, Peter A ; Phelps, Katherine J ; Darehshouri, Anza ; Xu, Lin ; Fisher, Edward A. ; Ge, Wuping ; Mineo, Chieko ; Shaul, Philip W. / SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis. In: Nature. 2019.
@article{e76d71f0d6134aa0b606997fee255549,
title = "SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis",
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.",
author = "Linzhang Huang and Chambliss, {Ken L.} and Xiaofei Gao and Yuhanna, {Ivan S.} and Erica Behling-Kelly and Sonia Bergaya and Mohamed Ahmed and Michaely, {Peter A} and Phelps, {Katherine J} and Anza Darehshouri and Lin Xu and Fisher, {Edward A.} and Wuping Ge and Chieko Mineo and Shaul, {Philip W}",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41586-019-1140-4",
language = "English (US)",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis

AU - Huang, Linzhang

AU - Chambliss, Ken L.

AU - Gao, Xiaofei

AU - Yuhanna, Ivan S.

AU - Behling-Kelly, Erica

AU - Bergaya, Sonia

AU - Ahmed, Mohamed

AU - Michaely, Peter A

AU - Phelps, Katherine J

AU - Darehshouri, Anza

AU - Xu, Lin

AU - Fisher, Edward A.

AU - Ge, Wuping

AU - Mineo, Chieko

AU - Shaul, Philip W

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85064905674&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064905674&partnerID=8YFLogxK

U2 - 10.1038/s41586-019-1140-4

DO - 10.1038/s41586-019-1140-4

M3 - Letter

C2 - 31019307

AN - SCOPUS:85064905674

JO - Nature

JF - Nature

SN - 0028-0836

ER -