Hypoxia enhances lipid uptake in macrophages: role of the scavenger receptors Lox1, SRA, and CD36.

Abstract

OBJECTIVES:

The core of advanced atherosclerotic plaques turns hypoxic as the arterial wall thickens and oxygen diffusion capacity becomes impaired. Macrophage-derived foam cells play a pivotal role in atherosclerotic plaque formation by expressing scavenger receptors that regulate lipid uptake. However, the role of hypoxia in scavenger receptor regulation remains incompletely understood.

METHODS AND RESULTS:

Using RT-qPCR, flow cytometry and immunoblotting, we found that mRNA and protein expression levels of the scavenger receptor A (SRA) and the cluster of differentiation 36 (CD36) were upregulated by oxidized low-density lipoprotein (oxLDL), but decreased following exposure of macrophages to hypoxia. In contrast, lectin-like oxLDL receptor (Lox-1) mRNA and protein levels were upregulated under hypoxic conditions. Flow cytometry confirmed the increased lipid content in macrophages after exposure to 0.2% oxygen and the hypoxia-mimetic dimethyloxalylglycine (DMOG). Antibody-mediated blocking of Lox-1 receptor decreased the hypoxic induction of oxLDL uptake and lipid content. RNAi-mediated knock-down of hypoxia-inducible factor (HIF)-1α in macrophages attenuated the hypoxic induction of Lox-1.

CONCLUSIONS:

Hypoxia increases lipid uptake into macrophages and differentially regulates the expression of oxLDL receptors. Lox-1 plays a major role in hypoxia-induced foam cell formation which is, at least in part, mediated by HIF-1α.

• Authors: Margot Crucet, Sophia J A Wüst, Patrick Spielmann, Thomas F Lüscher, Roland H Wenger, Christian M Matter
• Journal: Atherosclerosis (Atherosclerosis) Vol. 229 Issue 1 Pg. 110-7 (Jul 2013) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 23706521 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Chemical References

• Antibodies, Blocking
• CD36 Antigens
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Lipoproteins, LDL
• Msr1 protein, mouse
• Olr1 protein, mouse
• RNA, Messenger
• Scavenger Receptors, Class A
• Scavenger Receptors, Class E
• oxidized low density lipoprotein
• Cholesterol

Topics

• Animals
• Antibodies, Blocking (pharmacology)
• Atherosclerosis (metabolism, physiopathology)
• Biological Transport (physiology)
• CD36 Antigens (metabolism)
• Carcinoma, Hepatocellular
• Cell Line, Tumor
• Cholesterol (metabolism)
• Foam Cells (metabolism)
• Gene Knockdown Techniques
• Hypoxia (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Lipid Metabolism (physiology)
• Lipoproteins, LDL (metabolism)
• Liver Neoplasms
• Macrophages (cytology, metabolism)
• Mice
• RNA, Messenger (metabolism)
• Scavenger Receptors, Class A (genetics, metabolism)
• Scavenger Receptors, Class E (genetics, immunology, metabolism)