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

Author

Listed:
  • 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
    University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Ivan S. Yuhanna

    (University of Texas Southwestern Medical Center)

  • Erica Behling-Kelly

    (University of Texas Southwestern Medical Center
    College of Veterinary Medicine, Cornell University)

  • Sonia Bergaya

    (New York University School of Medicine
    New York University School of Medicine
    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
    University of Texas Southwestern Medical Center)

  • Edward A. Fisher

    (New York University School of Medicine
    New York University School of Medicine
    New York University School of Medicine)

  • Woo-Ping Ge

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Chieko Mineo

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Philip W. Shaul

    (University of Texas Southwestern Medical Center)

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.

Suggested Citation

  • 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. Fish, 2019. "SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis," Nature, Nature, vol. 569(7757), pages 565-569, May.
    • Handle: RePEc:nat:nature:v:569:y:2019:i:7757:d:10.1038_s41586-019-1140-4
    DOI: 10.1038/s41586-019-1140-4
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    Citations

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    Cited by:

    1. Seung Hyun Lee & Nayoung Kim & Minkyu Kim & Sang-Ho Woo & Inhee Han & Jisu Park & Kyeongdae Kim & Kyu Seong Park & Kibyeong Kim & Dahee Shim & Sang-eun Park & Jing Yu Zhang & Du-Min Go & Dae-Yong Kim , 2022. "Single-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    2. Anastasia Sacharidou & Ken Chambliss & Jun Peng & Jose Barrera & Keiji Tanigaki & Katherine Luby-Phelps & İpek Özdemir & Sohaib Khan & Shashank R. Sirsi & Sung Hoon Kim & Benita S. Katzenellenbogen & , 2023. "Endothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Juan Pang & Fitore Raka & Alya Abbas Heirali & Weijuan Shao & Dinghui Liu & Jianqiu Gu & Jia Nuo Feng & Chieko Mineo & Philip W. Shaul & Xiaoxian Qian & Bryan Coburn & Khosrow Adeli & Wenhua Ling & Ti, 2023. "Resveratrol intervention attenuates chylomicron secretion via repressing intestinal FXR-induced expression of scavenger receptor SR-B1," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. 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 , 2023. "Macrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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