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

Linzhang Huang1, Ken L Chambliss1, Xiaofei Gao2,3,4,5

  • 1Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Nature
|April 26, 2019
PubMed

Insights

Scavenger receptor SR-B1 in endothelial cells actively transports LDL cholesterol into artery walls, promoting atherosclerosis. This finding challenges passive LDL entry and suggests new therapeutic targets for cardiovascular disease.

Area of Science:

  • Cardiovascular Biology
  • Endothelial Cell Biology
  • Atherosclerosis Research

Background:

  • Atherosclerosis, a major cause of heart attack and stroke, begins with low-density lipoprotein (LDL) cholesterol entering artery walls.
  • The precise mechanism of LDL entry into the artery wall remains incompletely understood.

Purpose of the Study:

  • To investigate the role of scavenger receptor class B type 1 (SR-B1) in endothelial cells in mediating LDL entry into arteries.
  • To elucidate the molecular mechanisms by which SR-B1 facilitates LDL transport and promotes atherosclerosis.

Main Methods:

  • Studies in mouse models to assess SR-B1 function in endothelial cells.
  • In vivo colocalization studies of LDL and SR-B1.
  • Investigation of the interaction between SR-B1, dedicator of cytokinesis 4 (DOCK4), and RAC1 signaling.
  • Analysis of SR-B1 and DOCK4 expression in mouse and human atherosclerotic arteries.

Main Results:

  • Endothelial SR-B1 mediates LDL delivery into arteries and accumulation by macrophages, driving atherosclerosis.
  • LDL particles colocalize with SR-B1 in endothelial intracellular vesicles.
  • SR-B1-mediated LDL transcytosis requires direct binding and a specific cytoplasmic domain interacting with DOCK4, which activates RAC1.
  • SR-B1 and DOCK4 expression are upregulated in atherosclerosis-prone areas and human atherosclerotic arteries.

Conclusions:

  • Endothelial SR-B1 actively transports LDL into artery walls, challenging the passive diffusion model of atherogenesis.
  • Targeting endothelial LDL delivery via SR-B1 inhibition presents a novel therapeutic strategy for cardiovascular disease.

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